pazopanib and Carcinoma--Renal-Cell

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.

Topics: Angiogenesis Inhibitors; Anilides; Axitinib; Carcinoma, Renal Cell; Drug Interactions; Humans; Indazoles; Kidney Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib

Most contemporary metastatic renal-cell carcinoma patients receive first-line immunotherapy and tyrosine kinase inhibitor (TKI) combination or immunotherapy-immunotherapy combination, as first-line standards of care. However, second-line therapy choices are less well established. To address this void, we examined existing evidence supporting second and subsequent-line treatment options after immunotherapy-based combination therapy.. Evidence regarding efficacy of second-line therapy after immunotherapy-based combination is mainly retrospective, except for axitinib, which is the only TKI with prospective efficacy data in this setting. Cabozantinib demonstrated excellent second-line progression-free survival (PFS) that remained in third or later line use, albeit based on small numbers of observations. Moreover, pazopanib demonstrated excellent PFS, but showed wider variability in PFS rates. Sunitinib's PFS rates appeared lower than for axitinib, cabozantinib or pazopanib. Finally, inhibitors of the mammalian target of rapamycin pathway appeared to offer even lower efficacy than any TKI after immunotherapy-based therapy combinations.. All available contemporary evidence about TKI efficacy after immunotherapy-based therapy combinations is based on institutional studies. No major differences in efficacy for the examined TKIs after immunotherapy-based combination therapies were recorded. In general, these showed similar efficacy to their efficacy data recorded in first-line.

Topics: Anilides; Axitinib; Carcinoma, Renal Cell; Drug Therapy, Combination; Humans; Immunotherapy; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sulfonamides; TOR Serine-Threonine Kinases

Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.. To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.. We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.. We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.. Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.. We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 mon. Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Axitinib; Bevacizumab; Bias; Carcinoma, Renal Cell; Everolimus; Humans; Indazoles; Ipilimumab; Kidney Neoplasms; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Quinolines; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Cancer treatment has changed dramatically with the development of oral targeted therapies. Pazopanib, an oral VEGF tyrosine kinase inhibitor, is currently approved for advanced renal cell carcinoma, advanced soft tissue sarcoma, and is being studied for various tumor types. Due to the potential of increased exposure to pazopanib when crushed, pazopanib should be given as an intact whole tablet. Thus, in patients with difficulty swallowing medications or feeding tubes, pazopanib is usually not considered to be an option. Here, we describe two cases which show the administration of crushed pazopanib was feasible and had apparent clinical activity.

Topics: Adult; Aged; Carcinoma, Renal Cell; Chordoma; Female; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Skull Base Neoplasms; Sulfonamides

Drug regulators such as the US Food and Drug Administration (FDA) make decisions about drug approvals based on benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision making about new drugs to treat renal cell carcinoma (RCC). Fifteen FDA decisions on RCC drugs based on clinical trials whose results were published from 2005 to 2018 were identified and analyzed. The benefits and risks of the new drug in each clinical trial were quantified relative to comparators (typically the control arm of the same clinical trial) to estimate whether the benefit-risk was positive or negative. A sensitivity analysis was demonstrated using pazopanib to explore the magnitude of uncertainty. FDA approval decision outcomes for the clinical trials assessed were consistent and logical using this benefit-risk framework.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Decision Making; Drug Approval; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Risk Assessment; Sulfonamides; United States; United States Food and Drug Administration

Topics: Aged; Antineoplastic Agents, Immunological; Axons; Carcinoma, Renal Cell; Drug Substitution; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Lymphatic Metastasis; Male; Motor Neurons; Nivolumab; Paraparesis; Polyneuropathies; Pyrimidines; Skin Neoplasms; Sulfonamides

Pazopanib is a protein tyrosine kinase inhibitor that limits tumor growth through angiogenesis inhibition. The use of other protein tyrosine kinase inhibitors, specifically sunitinib, within non-clear cell renal cell carcinoma (nccRCC) has led to increased survival with a decreased adverse event profile. The data for the treatment of nccRCC is limited, with most studies evaluating the use of sunitinib. Therefore, the evaluation of pazopanib is of particular clinical interest in the treatment of nccRCC. The objective of this systematic review was to assess the efficacy and safety of pazopanib for nccRCC. PubMed (1946 to April 2019) and Embase (1947 to April 2019) were queried using the search term combination: protein tyrosine kinase inhibitor or pazopanib and non clear cell renal cell carcinoma or non-clear cell renal cell carcinoma. Studies evaluating clinical outcomes of pazopanib for nccRCC were included, represented by 3 retrospective cohort studies and 1 single-arm, open-label prospective study. In patients with advanced or metastatic nccRCC, treatment with pazopanib resulted in positive effects for multiple markers of efficacy, including progression-free survival, overall survival, and objective response rates. The median duration of follow-up ranged from 11.8 months to 24.4 months. Pazopanib was well-tolerated in most studies. The most commonly reported adverse events were fatigue, diarrhea, and hypertension. Pazopanib appears to be an effective and safe option for the treatment of advanced or metastatic nccRCC. Future investigation with larger randomized controlled trials is warranted to further define the role of pazopanib in patients with nccRCC.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials as Topic; Diarrhea; Fatigue; Humans; Hypertension; Indazoles; Kidney Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011.. The objective of this study was to perform an updated review by synthesizing economic studies related to the treatment of RCC that have been published since the previous review.. We performed a literature search in PubMed, EMBASE, and the Cochrane Library, covering English-language studies published between June 2010 and August 2018. We categorized these articles by type of analyses [cost-effectiveness analysis (CEA), cost analysis, and cost of illness (COI)] and treatment setting (cancer status and treatment), discussed findings from these articles, and synthesized information from each article in summary tables.. We identified 52 studies from 2317 abstracts/titles deemed relevant from the initial search, including 21 CEA, 23 cost analysis, and 8 COI studies. For localized RCC, costs were found to be positively associated with the aggressiveness of the local treatment. For metastatic RCC (mRCC), pazopanib was reported to be cost effective in the first-line setting. We also found that the economic burden of RCC has increased over time.. RCC continues to impose a substantial economic burden to the healthcare system. Despite the large number of treatment alternatives now available for advanced RCC, the cost effectiveness and budgetary impact of many new agents remain unknown and warrant greater attention in future research.

Topics: Carcinoma, Renal Cell; Cost of Illness; Cost-Benefit Analysis; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Time Factors

Sunitinib and pazopanib are extensively used as first-line treatment of metastatic renal cell carcinoma (mRCC). We performed this meta-analysis to assess the anti-tumor effectiveness, toxicity, and total costs of the two drugs among patients with mRCC/advanced RCC (aRCC).. PubMed, ScienceDirect, Scopus, Web of Science, Ovid MEDLINE, the Cochrane Library, Embase, and Google Scholar were searched to obtain eligible articles. The endpoints included progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and per-patient-per-month (PPPM) costs.. We included 14 medium- to high-quality studies. Both drugs were valid for mRCC/aRCC, with equivalent PFS (hazard ratio (HR) =1.06, 95% confidence interval [CI]: 0.98-1.15, P = 0.13), OS (HR = 0.92, 95% CI: 0.79-1.07, P = 0.29), objective response rate (ORR, risk ratio (RR) =1.03, 95% CI: 0.93-1.13, p = 0.58), and disease control rate (DCR, RR = 1.03, 95% CI: 0.94-1.22, P = 0.54). Sunitinib had more dosage reductions and higher PPPM (weighted mean difference = - 1.50 thousand US dollars, 95% CI: - 2.27 to - 0.72, P = 0.0002). Furthermore, more incidences of severe fatigue, thrombocytopenia, and neutropenia were recorded for sunitinib, but pazopanib had more liver toxicity. In subgroup analysis, studies from the US reported longer OS (HR = 0.86, 95% CI: 0.77-0.95, P = 0.004) and higher ORR (RR = 1.24, 95% CI: 1.03-1.51, P = 0.03).. Pazopanib provides equivalent anti-tumor effectiveness and lower PPPM as compared with sunitinib for mRCC/aRCC. Great care should be given to pazopanib-treated patients with abnormal liver function. Nevertheless, more large-scale, high-quality studies are required.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Fatigue; Health Care Costs; Humans; Indazoles; Kidney Neoplasms; Liver; Middle Aged; Neutropenia; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Thrombocytopenia; Treatment Outcome

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Quinolines; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

A systematic review was conducted to identify real world studies reporting outcomes after first-line pazopanib in patients with metastatic renal cell carcinoma. Studies had to be observational and report survival data in terms of progression-free survival and overall survival in order to conduct meta-analysis techniques. These real-world data were compared to those obtained in the phase II and III randomized controlled trials of pazopanib. Real world evidence showed that the clinical and safety outcomes were consistent with those observed in the clinical trials despite the inclusion of unselected patients with a wide spectrum of prognostic features and comorbidities. Similarly to the results of the pivotal studies, good prognosis patients had the most benefit from pazopanib. Further investigation is needed to complement evidence from clinical trials, in particular focused on patient-centered outcomes.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Survival Analysis

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents, Immunological; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Clinical Trials as Topic; CTLA-4 Antigen; Humans; Indazoles; Ipilimumab; Kidney Neoplasms; Nephrectomy; Nivolumab; Programmed Cell Death 1 Receptor; Pyridines; Pyrimidines; Sulfonamides

As no meta-analyses have evaluated tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma (RCC), the aim was to evaluate the benefit of sunitinib and pazopanib in the adjuvant setting.. This meta-analysis included all Phase III randomized controlled trials evaluating adjuvant sunitinib and pazopanib in high-risk RCC. Primary outcome was the comparison of disease-free survival (DFS) between tyrosine kinase inhibitors and placebo.. There was a tendency for significant overall effect of both sunitinib and pazopanib on DFS (hazard ratio: 0.85; 95% confidence interval: 0.72-1.01; p = 0.06). There was no significant difference between the effect of sunitinib and pazopanib on DFS (p = 0.51;  I. Pazopanib and sunitinib could prolong DFS in the adjuvant treatment of high-risk RCC and seem equally effective in this setting.

Topics: Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Humans; Indazoles; Indoles; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sulfonamides; Sunitinib

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cardiovascular Diseases; Cardiovascular System; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Risk Assessment; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome

Topics: Anilides; Brain Neoplasms; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Magnetic Resonance Imaging; Middle Aged; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics of pazopanib and see how these aspects are linked to clinical practice.. A non-exhaustive systematic review was conducted according to the three topics. No publication restrictions were imposed and the selected languages were Spanish and English. After that, a summary of the main results and findings of the review was presented and discussed during three meetings (one for each topic) with 13 medical oncologists that usually treat mRCC. At these meetings, a questionnaire on the first-line use of pazopanib in clinical practice was also drawn up. After the meetings, the questionnaire was completed by 60 specialist medical oncologists in renal cancer.. The efficacy and safety of pazopanib have been demonstrated in several clinical trials, and subsequently confirmed in studies in real-world clinical practice. In addition to its clinical benefit and good safety profile, quality of life results for pazopanib, which compare favorably to sunitinib, make it a good option in the first-line treatment of patients. Special populations have been included in studies conducted with pazopanib, and it is safe for use in elderly patients, poor functional status, kidney failure, and mild or moderate hepatic impairment, and in patients with concomitant cardiovascular disease. The results of the questionnaire have shown that pazopanib is perceived as an effective drug, in which quality of life (QoL) outcomes are valued above all.. This paper offers a comprehensive and critical summary of efficacy, tolerability, and pharmacokinetics of pazopanib in the treatment of mRCC. Pazopanib is an effective treatment with an acceptable safety profile. Its QoL and tolerability results offer certain advantages when compared with other therapeutic alternatives, and its use appears to be safe in different patient profiles.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Quality of Life; Sulfonamides; Treatment Outcome

Adjuvant treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor in renal cell carcinoma after nephrectomy has been reported through three clinical trials: S-TRAC, ASSURE and PROTECT. Only S-TRAC has been significantly positive on primary end-point disease-free survival under sunitinib compared to placebo, whereas ASSURE and PROTECT did not show any gain under sunitinib, sorafenib or pazopanib. This short review presents the differences between the trials and provides hypotheses on why S-TRAC may have been positive.

Topics: Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Progression-Free Survival; Pyrimidines; Sorafenib; Sulfonamides; Sunitinib

HOW TO CHOOSE THE APPROPRIATE SECOND-LINE TREATMENT?: The treatment of advanced or metastatic renal cell cancer (RCC) has dramatically improved in the past ten years. In the second-line setting, for patients who progressed on prior antiangiogenic therapy (mainly the VEGFR tyrosine kinase inhibitors (TKI) sunitinib or pazopanib), axitinib and everolimus have been recommended. Since 2015, other drugs have proven their efficacy and are currently considered the standard of care: cabozantinib (TKI that targets VEGFR, MET and AXL) and nivolumab (first anti-PD-1 check point inhibitor). Lenvatinib has also demonstrated promising results in association with everolimus, but this combination is not available in France. The optimal treatment choice for a given patient is challenging for the clinician when facing multiple options. In this article, we review the efficacy, safety and quality of life results of the main pivotal clinical studies involving advanced or metastatic RCC in the second-line setting, to help clinicians in selecting the most appropriate treatment. Beyond that, it is important to define all the sequencing strategy for patients to successively receive all the drugs that have demonstrated an increase in overall survival.

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Immunotherapy; Indazoles; Kidney Neoplasms; Nivolumab; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Sulfonamides; Sunitinib

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and is known to be the 10th most common type of cancer in the world. Most of the currently available RCC drugs are tyrosine kinase inhibitors (TKIs). However, combination therapies of TKIs and immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors are the focus of most of the final stage clinical trials. Meanwhile, other small molecule therapies for RCC that target indoleamine-2,3-dioxygenase (IDO1), glutaminase, C-X-C chemokine receptor 4 (CXCR4), and transglutaminase 2 (TG2) are emerging as the next generation of therapeutics. In this review, these three major streams for the development of small molecule drugs for RCC are described.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Discovery; Humans; Kidney; Kidney Neoplasms; Molecular Targeted Therapy; Small Molecule Libraries

Pazopanib (Votrient®), an orally administered multi-targeted tyrosine kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β, and the stem cell factor receptor c-Kit, is approved in the EU, the USA and other countries for the treatment of advanced renal cell carcinoma (RCC). In randomized controlled trials in patients with advanced, predominantly clear-cell RCC, pazopanib significantly improved progression-free survival (PFS) compared with placebo in both treatment-naïve and cytokine-pretreated patients and, as a first-line therapy, was noninferior to intermittent sunitinib with respect to PFS. However, pazopanib had a tolerability profile that was distinguishable from that of sunitinib, based on lower incidences of most adverse events, particularly those associated with discomfort, such as fatigue, hand-foot syndrome and stomatitis. Consistent with this, health-related quality of life (HR-QOL) measures evaluating fatigue, hand/foot soreness and mouth/throat soreness significantly favoured pazopanib over sunitinib. In addition, significantly more patients expressed a preference for pazopanib over sunitinib, primarily because of better overall HR-QOL and less fatigue. Efficacy and tolerability findings from these prospective clinical trials have been substantiated by evidence from a number of retrospective studies evaluating unselected real-world patients with metastatic RCC who received pazopanib (or sunitinib) as a first-line therapy. Thus, data from clinical trials supplemented with that from clinical practice support the use of pazopanib as a standard or alternative first-line treatment for advanced or metastatic RCC.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Humans; Indazoles; Male; Pyrimidines; Sulfonamides

Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).. A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.. Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.. Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Decision Trees; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Nivolumab; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Topics: Axitinib; Carcinoma, Renal Cell; Everolimus; Fatal Outcome; Female; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Magnetic Resonance Imaging; Middle Aged; Nephrotic Syndrome; Posterior Leukoencephalopathy Syndrome; Pyrimidines; Sulfonamides

While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.. To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.. Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.. The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.. This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.. We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

Topics: Anilides; Antineoplastic Agents; Axitinib; Benzimidazoles; Bevacizumab; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Pyrrolidinones; Quinolines; Quinolones; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

This systematic review and meta-analysis was accomplished with the purpose of evaluating the risk of encountering selected hair changes in patients with cancer receiving pazopanib.. We favored relevant prospective randomized phase II and III trials that assessed pazopanib in patients with cancer, depicting various hair-related changes, as eligible for inclusion.. After elimination of ineligible studies, a total of 11 clinical trials were regarded as eligible for the meta-analysis. The relative risk of all-grade alopecia and hair color changes was 1.75 (95% confidence interval, 1.33-2.31; P < .0001) and 4.54 (95% confidence interval, 3.67-5.62; P < .00001), respectively. Subgroup analyses of hair color changes according to the type of cancer treated revealed significant differences between renal cell carcinoma and non-renal cell carcinoma studies (P = .01).. Our meta-analysis has established that pazopanib-based treatment can be significantly correlated to an elevated risk of all grade alopecia and hair color changes compared with controls.

Topics: Alopecia; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Hair Color; Humans; Indazoles; Kidney Neoplasms; Male; Prospective Studies; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance. Localized RCC can be successfully managed with surgery, whereas metastatic RCC is refractory to conventional chemotherapy. However, over the past decade, marked advances in the treatment of metastatic RCC have been made, with targeted agents including sorafenib, sunitinib, bevacizumab, pazopanib and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mechanistic target of rapamycin complex 1 (mTORC1), being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies, such as nivolumab, have also been added to the armamentarium for metastatic RCC. Here, we provide an overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy.

Topics: Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Kidney; Kidney Diseases; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Quality of Life; Risk Factors; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Over the last few years, the most recent advances of the molecular mechanisms involved in renal cell carcinoma have led to the use of new drugs targeting VEGF, such as bevacizumab plus interferon, sorafenib, sunitinib, pazopanib, and axitinib, or the mTOR, such as temsirolimus and everolimus. The purpose of this review is to analyze the results of Phase III trial with these targeted agents, and on the management of the treatment and, in particular, when to start and to stop therapy and the use of alternative schedule of sunitinib. Recent developments in immunotherapy are also discussed.

Topics: Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The effect of first targeted therapy on outcomes with second targeted therapy for metastatic renal cell carcinoma is not well known. The purpose of this study was to compare outcomes for patients receiving a second targeted therapy with everolimus by type of first targeted therapy.. Data were drawn from 3 separate retrospective chart reviews conducted in 2011, 2012, and 2014. Inclusion criteria and study design were similar across the 3 studies. To be included in this analysis, patients had to meet the following criteria: aged ≥ 18 years; received first targeted therapy with pazopanib, sunitinib, or sorafenib; and received second targeted therapy with everolimus. Overall survival, time to treatment failure, and time to treatment discontinuation outcomes were measured from second targeted therapy initiation. Outcomes were compared among treatment groups by Cox proportional hazard models adjusting for demographic and clinical characteristics. Hazard ratios for overall survival, time to treatment failure, and time to treatment discontinuation obtained from the 3 chart reviews were synthesized in meta-analyses.. Of 696 patients treated with everolimus as second targeted therapy, 605 patients received first targeted therapy with sunitinib/sorafenib and 91 with pazopanib. After synthesizing the hazard ratios from all studies in meta-analyses, there were no significant differences in study outcomes between patients receiving sunitinib/sorafenib versus those receiving pazopanib as first targeted therapy.. There were no significant differences among outcomes while receiving second targeted therapy with everolimus for patients treated with pazopanib versus sunitinib/sorafenib as first targeted therapy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

Sporadic data are available about pazopanib use in patients with metastatic renal cell carcinoma (mRCC) undergoing dialysis and no systematic review has been previously performed about this issue.. The objective of the present mini-review is to provide an overview of clinical outcomes of pazopanib in this population, in order to support the clinical oncologist for the treatment choice and management.. All the literature ever published about mRCC dialysis patients receiving pazopanib, until August 2015, was evaluated: only two case series emerged from our search and one more patient from our department was also included, with a total of 11 mRCC dialysis patients overall. Moreover, we described our case of intrapatient dose titration of pazopanib during dialysis.. The continued treatment schedule, the short half-life, the predominantly hepatic metabolism, the wide possibility of dose modulation, the favorable tolerability profile and the similar efficacy respect to sunitinib represent factors in favor of pazopanib as first line mRCC treatment in dialysis patients. The knowledge and the good management of toxicity during pazopanib treatment can lead, also in dialysis patients, to the best and longest application of the drug, taking into account the concept of a dose escalation guided by toxicity as a marker of efficacy. The review, together with our single case report, confirmed the efficacy, the good tolerability and the maneuverability of pazopanib treatment in mRCC patients undergoing dialysis.

Topics: Adult; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Half-Life; Humans; Indazoles; Kidney Failure, Chronic; Kidney Neoplasms; Male; Pyrimidines; Renal Dialysis; Sulfonamides; Treatment Outcome

In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine kinase inhibitors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Quality of Life; Quinazolines; Quinolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Not only has the use of tyrosine kinase inhibitors (TKI) for the treatment of metastatic renal cell carcinomas (mRCC) changed the therapeutic options for this disease significantly, but with the occurrence of typical side effects this therapy also poses a challenge for the treating physician. Fatigue und hypothyroidism are two common side effects of TKI therapy that can often appear simultaneously. By reducing the patients' quality of life these side effects often lead to a discontinuation of therapy. With this review we want to give the treating physician an overview of the classification and the specific treatment of TKI-induced fatigue and hypothyroidism in order to maximize patients' compliance and the therapeutic efficacy of TKI therapy.

Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Disease Progression; Enzyme Inhibitors; Fatigue; Humans; Hypothyroidism; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Quality of Life; Sorafenib; Sulfonamides; Sunitinib

The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include pazopanib as a second-line treatment option. It would therefore be of interest to determine the efficiency of pazopanib in this setting in terms of the partial response rate (PRR), disease control rate (DCR), and progression-free survival (PFS).. Peer-reviewed clinical reports without language restriction, both full papers and conference abstracts, which assessed the second-line use of pazopanib following failure of first-line non-cytokine-targeted therapy, were included. After the literature retrieval, we conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-compliant systematic review of the literature and meta-analysis of the size of the effect of each outcome measure (PRR, DCR, and PFS). The effect size and 95 % confidence interval (CI) were calculated using fixed-effect or random-effects models based on the heterogeneity represented by I(2) of selected studies. Meta-analysis forest plots with a fixed-effect model showing the PRR and DCR were created.. Our results show that there are no available comparative studies on pazopanib second-line treatment. Only phase II trials or retrospective analysis reports were retrievable. Six studies (comprising 217 patients) were included in the qualitative and quantitative analysis. Pazopanib as a second-line treatment resulted in a PRR of 23 % (95 % CI, 17-31 %; I(2) = 52.6 %) and a DCR of 73 % (95 % CI, 65-80 %; I(2) = 0.00 %). The meta-analysis with fixed-effect model revealed that PFS was 6.5 months (95 % CI, 5.6-7.5 months; I(2) = 86.2 %).. In conclusion, the effectiveness and indication of pazopanib for use in the second-line setting has not yet been examined in-depth; however, this meta-analysis has shown that the treatment effects in terms of PRR, DCR, and PFS may be similar to other well-studied second-line targeted therapies. Rigorous comparative phase III trials testing this hypothesis are required.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome

In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of compounds that suppressed vascular endothelial growth factor receptor-2 (VEGFR-2). As other tyrosine kinase inhibitors (TKI), pazopanib is not totally specific for one target since it also inhibits stem-cell factor receptor (cKIT), platelet-derived growth factor receptors (PDGFRα, β), VEGFR-1 and -3. Areas covered: Clinical pharmacology, drug-drug interactions and safety data published on pazopanib, between January 2006 and April 2016, are reviewed. Expert opinion: This new therapy has been shown to improve progression-free survival compared with previous approaches, in renal cell cancer and soft-tissue sarcoma. However, some specific sub-populations, such as elderly patients, patients with brain metastases or with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 or comorbidities, are poorly represented in pivotal pazopanib phase III studies. Pazopanib meets criteria defining therapies as candidates for therapeutic drug monitoring: large intra- and inter-patient pharmacokinetic variability, potential pharmacokinetic drug-drug interactions, pharmacokinetic/pharmacodynamic relationship and narrow therapeutic index. Knowledge of predictors that can be used to guide dosing regimens in the target population and in special populations needs to be improved.

Topics: Aged; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Interactions; Drug Monitoring; Humans; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Pyrimidines; Sarcoma; Sulfonamides

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; DNA-Binding Proteins; Everolimus; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; MicroRNAs; Molecular Targeted Therapy; Mutation; Niacinamide; Nivolumab; Nuclear Proteins; Phenylurea Compounds; Precision Medicine; Prognosis; Pyridines; Pyrimidines; Pyrroles; Quinolines; Receptors, CCR4; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR) complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy treatment for patients with mRCC. In the majority of trials evaluating targeted therapy, patients were stratified according to Memorial Sloan Kattering Cancer Center (MSKCC) risk model and the recommendation of targeted treatment based on risk features. In first-line setting (no previous treatment), sunitinib, pazopanib, or bevacizumab plus IFN-α were recommended as treatment options for patient with favorable- or intermediate- risk features and clear cell histology. Patients who progressed after previous cytokine therapy would have sorafenib or axitinib as treatment options. Clear-cell mRCC with favorable- or intermediate- risk features and failure with first-line TKI therapy might be treated with sorafenib, everolimus, temsirolimus or axitinib. However, the current evidence did not show the best treatment sequencing after first-line TKI failure. In patients with poor-risk clear-cell and non-clear cell mRCC, temsirolimus was the treatment option supported by phase III clinical trial. In addition, several new drugs, nowadays, are still being investigated and waiting for the result of phase II or III clinical trial, and this might change the standard therapy for mRCC in the future.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Fatigue is the most common symptom associated with cancer and cancer treatment. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) of fatigue in patients (pts) with cancer treated with sorafenib (SO), sunitinib (SU) and pazopanib (PZ). PubMed databases were searched for articles published till August 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR and 95% confidence intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. Fifteen studies were included in our analysis. A total of 6,996 pts was enrolled: 2,260 had renal cell carcinomas (RCC), 1,691 non-small cell lung cancers, 1,290 breast cancers, 823 hepatocellular carcinomas, 362 soft tissue sarcomas, 304 gastrointestinal solid tumors, 165 neuroendocrine tumors and 101 melanomas. When stratified by drug, SO registered lower incidence and RR of all and high-grade fatigue when compared to SU, whereas the difference between SO and PZ was significant only for all-grade fatigue (p < 0.001). The difference between SU and PZ was significant for high-grade (p < 0.001) but not for all-grade fatigue (p = 0.52). In RCC pts, PZ showed the lower incidence and RR of all and high-grade fatigue. The differences were significant for SU vs. SO (p < 0.001), SU vs. PZ (p < 0.001) and SO vs. PZ (p < 0.001). Treatment with SO, SU and PZ is associated with an increased incidence of fatigue in pts with cancer. Early and appropriate management is required to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Fatigue; Humans; Incidence; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Risk; Sorafenib; Sulfonamides; Sunitinib

Topics: Angiogenesis Inhibitors; Carcinogenesis; Carcinoma, Renal Cell; Disease Progression; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Nephrectomy; Nephrons; Organ Sparing Treatments; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

The incidence and mortality from renal cell cancer (RCC) is increasing. RCC tumors are particularly vascular in nature as a result of disruption of the VHL gene and/or its upstream pathway leading to upregulation of the hypoxia-inducible factor transcription factor. The hypoxia-inducible factor pathway drives angiogenesis by upregulating VEGF and bFGF, amongst other proangiogenic downstream target genes. Therapies which target angiogenesis have been successful in treating metastatic RCC (mRCC) and the receptor tyrosine kinase inhibitor, pazopanib, is licensed for first line treatment of mRCC. This review details the past, current and future roles of pazopanib in the treatment of mRCC.

Topics: Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

In patients with metastatic renal cell carcinoma and favourable or intermediate risk, sunitinib, pazopanib, and bevacizumab along with interferon have been recommended with identical evidence level I, recommendation grade A. In clinical practice, most physicians and patients are likely to favour an oral treatment (i.e., sunitinib or pazopanib). Choosing between those two tyrosine kinase inhibitors may prove challenging. Two randomized trials have been conducted to facilitate treatment choices, COMPARZ, and PISCES. We discuss below the design of these trials, their results, their potential interpretation, and their clinical implications for selecting treatment.. Both trials were reported to meet the primary endpoint (i.e., noninferiority of pazopanib versus sunitinib) and patient's preference of pazopanib over sunitinib. However, several methodological aspects have raised doubts about the reliability of these conclusions. Pitfalls include the patients selected for the final analysis, discrepancies of results between the per protocol and intention-to-treat populations, the time points at which quality of life and disease were assessed.. A rigorous head-to-head comparison of pazopanib versus sunitinib is yet to be performed. Clinical considerations and physicans' experience, rather than the reported results of these trials, may continue to influence treatment choices.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Patient Selection; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Risk Factors; Signal Transduction; Sulfonamides; Sunitinib; Time Factors; Treatment Outcome

A variety of therapeutic agents are currently available for the systemic treatment of metastatic renal cell carcinoma (mRCC). It was only when targeted treatment was developed in the past decade that a significant improvement was achieved in tumour therapy. This also led to the development of sequential treatment for mRCC.7 molecular targeted agents are available today (axitinib, bevacizumab/ IFNα, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus). Due to the individualisation of treatment it remains a challenge to choose the most appropriate drug in a given setting, with the choice being based on the knowledge of the relevant clinical data as well as individual patient parameters.During the recent past, efforts have been made to test different inhibitors or combinations without a major breakthrough. Instead, the development of novel specific immunotherapeutic approaches now heralds the next level of treatment in mRCC. The first significant trial results will be expected this year, and further trials for optimisation of treatment are warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Disease Progression; Everolimus; Humans; Imidazoles; Immunotherapy; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis

Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II-III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2-2.8) compared to 1.4% (95% CI, 0.7-2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2-3.8) in the bevacizumab group and 1.6% (95% CI, 0.1-2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85-2.73; p=0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indazoles; Indoles; Induction Chemotherapy; Interferons; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) in patients with cancer treated with these agents. PubMed databases were searched for articles published till May 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 6,447 patients were available for the meta-analysis; 2,260 had renal cell carcinoma (RCC) and 4,187, 1,691 non-small cell lung cancers, 599 hepatocellular cancers, 1,066 breast cancers, 165 neuroendocrine tumors, 304 gastrointestinal stromal tumors and 362 soft tissue sarcomas. Diarrhea was the most common GI event. When stratified by tumor type (RCC vs. non-RCC), the difference among the incidences of GI events was significant for diarrhea (p < 0.001) and vomiting (p = 0.006), that resulted higher in RCC patients. In RCC patients, sorafenib registered the lower incidence and RR of all grades GI events. The difference was statistically significant for sorafenib versus sunitinib-related all and high-grade events (p < 0.001) and for sorafenib versus pazopanib all grades GI events (p < 0.001) and high-grade anorexia (p < 0.001). Treatment with VEGFR TKIs sorafenib, sunitinib and pazopanib is associated with a significant increase in the risk of GI events in patients with cancer, and frequent clinical monitoring should be emphasized when managing these three and newer VEGFR TKIs.

Topics: Adverse Drug Reaction Reporting Systems; Carcinoma, Renal Cell; Clinical Trials as Topic; Diarrhea; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Incidence; Indazoles; Indoles; Liver Neoplasms; Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vomiting

Pazopanib (Votrient(®)) is an orally administered multi-tyrosine kinase inhibitor that is approved in the EU, the US and other countries for the treatment of advanced renal cell carcinoma. Pazopanib predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β, and the stem cell factor receptor c-Kit, resulting in inhibition of tumour angiogenesis, cell growth and survival. In randomized controlled trials in patients with advanced, predominantly clear-cell, renal cell carcinoma, progression-free survival (PFS) and the objective response rate were significantly greater in pazopanib recipients than in placebo recipients (VEG105192 trial), and pazopanib was noninferior to sunitinib with respect to PFS (COMPARZ study). In a patient-preference, crossover study involving 10 weeks of treatment with each drug (PISCES study), significantly more patients expressed a preference for pazopanib than for sunitinib, with their preference being based primarily on tolerability and quality-of-life issues. Health-related quality-of-life (HR-QOL) assessments generally favoured pazopanib over sunitinib in COMPARZ, and pazopanib did not cause deterioration in HR-QOL compared with placebo in VEG105192. Pazopanib caused less myelosuppression, hand-foot syndrome, mucositis/stomatitis, dysgeusia and fatigue than sunitinib, but more abnormal liver function tests. Therefore, pazopanib was noninferior to sunitinib with respect to efficacy in the treatment of advanced renal cell carcinoma, but had a differentiated tolerability profile, which affected HR-QOL and patient preference.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Proliferation; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Quality of Life; Sulfonamides

The role of angiogenesis in the physiopathology of renal cell carcinoma is fundamental. Strategies targeting angiogenesis have been developed including VEGF and VEGFR inhibitors for the treatment of metastatic renal cell carcinoma (mRCC), in first and second line. Pazopanib is an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor and c-KIT receptor. This treatment is a treatment option recommended for patients with mRCC, would be in first line or after cytokines failure. Pazopanib has been recently approved for patients with metastatic soft tissue sarcoma, after failure of at least one line of chemotherapy.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sarcoma; Sulfonamides

Based on improved clinical outcomes in randomized controlled clinical trials (RCTs) the FDA and EMA have approved bevacizumab with interferon, sunitinib, and pazopanib in the first-line treatment of low to intermediate risk metastatic clear cell renal cell carcinoma (mRCC). However, there is little comparative data to help in choosing the most effective drug among these agents.. We performed an indirect comparative effectiveness analysis of the pivotal RCTs of bevacizumab with interferon, sunitinib, or pazopanib compared to one another or interferon alone in first-line treatment of metastatic or advanced RCC. Endpoints of interest were overall survival (OS), progression free survival (PFS), and response rate (RR). Adverse events were also examined.. The meta-estimate of the hazard ratio (95% confidence interval) for OS for bevacizumab with interferon vs. interferon alone was 0.86 (0.76-0.97), for sunitinib vs. interferon alone was 0.82 (0.67-1.00), for pazopanib vs. interferon alone was 0.74 (0.57-0.97), for sunitinib vs. bevacizumab with interferon was 0.95 (0.75-1.20), for pazopanib vs. bevacizumab with interferon was 0.86 (0.64-1.16), and for pazopanib vs. sunitinib was 0.91 (0.76-1.08). Similarly, bevacizumab with interferon, sunitinib, or pazopanib had better PFS and RR than interferon alone. Sunitinib and pazopanib had better RR than bevacizumab with interferon and there was suggestive evidence pazopanib may outperform sunitinib in terms of RR.. Bevacizumab with interferon, sunitinib, and pazopanib are adequate first-line options in treatment of mRCC. Interferon alone should not be considered an optimal first-line treatment.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Interferons; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sulfonamides; Sunitinib; Survival Analysis

Skeletal involvement is common in patients with renal cell carcinoma (RCC): ∼30% of patients with metastatic RCC (mRCC) will develop bone metastases. Inhibition of vascular endothelial growth factor (VEGF) has been pursued as a therapeutic target in the treatment of metastatic clear-cell RCC (m-ccRCC). Tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, sorafenib, and the monoclonal antibody bevacizumab, became the therapy of choice for patients with m-ccRCC. Besides the undisputed efficacy of TKI in the treatment of m-ccRCC, the problem of metastatic bone disease still remains. There is evidence that the presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on survival and potentially on the outcome of VEGF-targeted therapy. Also, a relatively common practice in the treatment of such patients is bone-directed therapy with bisphosphonates (BPs). Recent evidence shows a potentially synergistic effect on efficacy but also the potential for increased toxicity of combining TKIs and BPs. This review article highlights the importance of this subject and aims to facilitate further research and optimize the treatment of this important and common group of RCC patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Renal Cell; Diphosphonates; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A; Zoledronic Acid

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Palliative Care; Protein Kinase Inhibitors; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases

With the introduction of multiple new targeted agents for the treatment of metastatic renal cell carcinoma, specific attention must be given to toxicities induced by these agents.. Agents with activity on the same target can have different toxicities, which might lead the clinician to select or individualize therapies. However, some data also support the concept of maximal tolerated dose as a marker of efficacy. Specific elements of these data are summarized and discussed in the paper.. Toxicity management is pivotal in individualized cancer care. This papers outlines some of the principles related to disease and toxicity management.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; Sunitinib

The introduction of therapy targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapomycin (mTOR) has significantly improved the outcome of patients with metastatic renal cancer. In this article a comprehensive overview of treatment choices for previously untreated patients with metastatic disease is given. Both established and emerging therapeutic options are discussed, as are prognostic factors predicting outcome.

Topics: Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib

Currently approved treatments for metastatic renal cell carcinoma (RCC) include vascular endothelial growth factor (VEGF)-blocking agents, mammalian target of rapamycin (mTOR) inhibitors, and cytokine therapy. In the near future, we are likely to add immune checkpoint blocking agents to this list. As we develop treatment platforms around each therapeutic class, determining which drug is best for a particular patient becomes increasingly important. At this point, we do not have validated predictive biomarkers for patients with RCC. Here, we discuss the logistical challenges surrounding biomarker development, summarize the current crop of biomarker candidates, and explore potential avenues for the development of more effective predictive tools for patients with advanced RCC.

Topics: Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Bevacizumab; Biomarkers, Tumor; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Renal Cell; Gene Dosage; Humans; Immunotherapy; Indazoles; Indoles; Kidney Neoplasms; Mutation; Neoplastic Cells, Circulating; Niacinamide; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Polymorphism, Genetic; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Von Hippel-Lindau Tumor Suppressor Protein

Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI (sunitinib or pazopanib) as initial therapy. Upon disease progression or intolerance, there are four orally administered agents approved in the second-line setting (including cytokine-refractory). However, head-to-head comparative trial data are limited. In this study, an indirect statistical comparison of safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus in second-line therapy mRCC.. A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials (RCTs) evaluating at least one of the four agents in second-line mRCC. Bayesian mixed treatment comparison models were fitted to assess relative effectiveness on multiple endpoints such as objective response rates, dose-limiting grade III/IV toxicities, treatment discontinuations and progression-free survival (PFS).. Four RCTs met the inclusion criteria. All four agents seem able to induce tumor shrinkage and to provide patients with a clinically meaningful PFS benefit. Axitinib was superior to pazopanib [hazard ratio (HR) 0.64; 95 % credible interval (95 % Crl) 0.42-0.96] and sorafenib (HR 0.70; 95 % Crl 0.57-0.87) in terms of PFS. However, axitinib was associated with an elevated risk of fatigue and to a lesser extent stomatitis.. Keeping in mind the caveats associated with cross-trial statistical comparisons, axitinib provides superior PFS relative to pazopanib and sorafenib. Everolimus, an mammalian target of rapamycin inhibitor, is mechanistically distinct from the other agents and remains a useful option for patient's post-anti-VEGFR TKI failure.

Topics: Antineoplastic Agents; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides

A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib.. Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI).. Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival (PFS), axitinib was superior compared with placebo (HR = 0.25, 95% CrI: 0.17 - 0.38), sorafenib (HR = 0.46, 95% CrI: 0.32 - 0.68) and pazopanib (HR = 0.47, 95% CrI: 0.26 - 0.85). An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib.. Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Female; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyrimidines; Randomized Controlled Trials as Topic; Sorafenib; Sulfonamides; Treatment Outcome; Young Adult

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of pazopanib hydrochloride (GlaxoSmithKline) to submit evidence of the clinical and cost effectiveness of the drug for the first-line treatment of advanced and/or metastatic renal cell carcinoma, as part of the Institute's single technology appraisal (STA) process. The Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The objective of this paper is to summarize the independent review and critique of the evidence submitted for the consideration of the NICE Appraisal Committee and NICE's subsequently issued guidance. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. For progression-free survival (PFS), there was a statistically significant longer survival for pazopanib compared with placebo (as assessed by the ERG, based upon the original manufacturer submission with a clinical cut-off date of 23 May 2008) [median 11.1 vs. 2.8 months; hazard ratio (HR) 0.40; 95 % CI 0.27, 0.60]. Data from the indirect comparison suggested that pazopanib had a greater survival than interferon alpha (IFN-α) [HR 0.512; 95 % CI 0.326, 0.802] but provided no evidence of any difference compared with sunitinib (HR 0.949; 95 % CI 0.575, 1.568). With regard to overall survival, 64 % (n = 99) of patients in the pazopanib arm and 63 % (n = 49) of patients in the placebo arm had died and a total of 51 % (n = 40) of placebo patients had crossed over to receive pazopanib. Although data were provided on an intention-to-treat basis, crossover between therapies made such data difficult to interpret. There was no evidence of any statistically significant difference between pazopanib and best supportive care (HR 0.501; 95 % CI 0.136, 2.348). In the indirect comparison, there were no statistically significant differences between pazopanib and IFN-α (HR 0.627; 95 % CI 0.173, 2.269) or between pazopanib and sunitinib (HR 0.969; 95 % CI 0.359, 2.608). Based upon the work presented including a 12.5 % discount for pazopanib, sunitinib was extendedly dominated by a co

Topics: Carcinoma, Renal Cell; Cost-Benefit Analysis; Decision Making; Drug Approval; Drug Costs; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Technology Assessment, Biomedical; United Kingdom

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC.

Topics: Anorexia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular System; Drug Eruptions; Europe; Everolimus; Evidence-Based Medicine; Gastrointestinal Tract; Humans; Hypothyroidism; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pneumonia; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Weight Loss; Wound Healing

Renal cell carcinoma (RCC) is the most common cancer in the kidneys. Until 2005, treatment options were limited to immunotherapy. Since that time, there have been numerous targeted therapy agents approved with improved efficacy toward RCC. Pazopanib is a multi-tyrosine kinase inhibitor that was approved by the US Food and Drug Administration in October 2009 and by the European Medicines Agency in June 2010 for the treatment of metastatic RCC.. The objective of this report was to review pazopanib's mechanism of action; pharmacologic, pharmacokinetic, and dynamic properties; potential drug interactions; and the results of clinical trials evaluating efficacy and tolerability associated with pazopanib for the treatment of RCC.. MEDLINE, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and therapeutic reviews (publication dates: 2000-January 1, 2012). Abstracts from the 2000 to 2011 meetings of the American Society of Clinical Oncology were searched for an updated safety profile and tolerability data of pazopanib in RCC. References from relevant articles were reviewed. Key search terms included pazopanib, Votrient, GW786034, renal cell carcinoma, adverse events, pharmacology, pharmacokinetic, and clinical trial.. Two clinical trials met the inclusion criteria for the use of pazopanib in RCC (a Phase II and a Phase III trial). Pazopanib is an inhibitor of numerous tyrosine kinases, including vascular endothelial growth factor receptor and platelet-derived growth factor receptors. It is involved in inhibiting signaling pathways, angiogenesis, and cell proliferation. Pazopanib was approved by the US Food and Drug Administration and the European Medicines Agency at the dose of 800 mg daily. Peak concentrations are achieved within 2 to 4 hours of this dose with a mean t(½) of 35 hours. The pharmacokinetic properties of pazopanib are affected by food as well as by crushing the tablet. A 2-fold increase in AUC was seen when pazopanib was administered with a high-fat meal as well as when crushing the tablet. Thus, pazopanib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Pazopanib is primarily metabolized by cytochrome P-450 3A4, and caution should be used with concomitant administration of cytochrome P-450 inducers and/or inhibitors. In a Phase III trial of pazopanib in metastatic RCC, pazopanib reportedly improved progression-free survival from a median of 4.2 to 9.2 months compared with placebo (P < 0.0001). The most common adverse effects of pazopanib were hypertension, hair depigmentation, diarrhea, nausea, anorexia, and vomiting. Many of the grade 3/4 toxicities were hepatic in nature, with elevations occurring in aspartate aminotransferase, alanine aminotransferase, and bilirubin.. Pazopanib is reportedly effective in the treatment of metastatic RCC. Although there are currently no direct comparisons between pazopanib and other tyrosine kinase inhibitors, the data suggest that pazopanib may be a first-line option in the treatment of RCC. The only Phase III trial of pazopanib suggests improvement of progression-free survival in RCC as well as tolerability in the selected population.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Interactions; Humans; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides; Treatment Outcome

This article reviews recent developments in the use of systemic targeted therapies for the treatment of advanced clear and nonclear cell renal cell carcinoma (RCC). The genetic/molecular basis of each form of RCC is discussed and current treatments and clinical trials are described.. The treatment of advanced RCC continues to be a major challenge for uro-oncologists. The rapid growth in therapeutic options has brought much needed improvements in overall and progression-free survival, although durable complete responses remain elusive. The recent identification of mutations in genes involved in chromatin remodeling will likely lead to the investigation of whether components of this critical process can also be valid therapeutic targets in clear cell RCC. Similarly, efforts to decipher the molecular mechanisms underlying nonclear cell variants of RCC are beginning to engender novel therapeutic strategies directed against these rarer forms of kidney cancer. Despite the availability of multiple treatment options, several challenges remain: selecting the best first-line or subsequent therapy for a given patient, the optimal sequencing of the various agents available, designing trials with appropriate comparison arms and endpoints, and identifying well tolerated and effective drug combinations.. Agents targeting the vascular endothelial growth factor and mammalian target of rapamycin pathways remain the mainstay in the management of metastatic RCC. Ongoing and future studies are expected to facilitate the development of therapeutic regimens that incorporate agents with improved tolerability and enhanced efficacy by continuing to capitalize on the strides made by basic and translational scientists in uncovering the mechanisms underlying the various forms of RCC.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Sorafenib; Sulfonamides; Tuberous Sclerosis; United States

In general, debulking neprhectomy is still considered for metastatic RCC patients with primary tumor in place, assuming good performance status. Initial systemic therapy should consider high-dose IL-2 for the highly select patient. One reason for initial consideration of this therapy is the less certain risk/benefit profile if employed after targeted therapy. Notably, due to its potential toxicity and emergence of new effective and more tolerable drugs, IL-2 has become a less favorable and subsequently a less utilized therapeutic tool in the current era. Otherwise, VEGF-targeted therapy is the treatment of choice, preferably on a clinical trial. Off trial, sunitinib has long been favored but pazopanib is gaining more use for tolerance pending the comparative trial. Continued VEGF targeting is favored by these authors given the underlying biology of RCC and the prospective clinical data, noting no direct comparison of mTOR and VEGF agents has yet occurred. Maintaining patient dose is critical and requires optimal supportive care and appreciation/early intervention for toxicity. Predictive biomarkers are desperately needed, and enrollment on clinical trials remains a priority to optimize patient outcome.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Nephrectomy; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Sorafenib; Sulfonamides

Pazopanib and axitinib are both U.S. Food and Drug Administration approved ATP-competitive inhibitors of the vascular endothelial growth factor receptor. Pazopanib and axitinib have been shown to be effective and tolerable treatment options for patients with metastatic renal cell cancer and therefore have enlarged the armamentarium for this disease. This concise drug review discusses the clinical benefits, clinical use, mechanism of action, bioanalysis, pharmacokinetics, pharmacogenetics, pharmacodynamics, drug resistance, toxicity, and patient instructions and recommendations for supportive care for these two drugs.

Topics: Angiogenesis Inhibitors; Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Meta-Analysis as Topic; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; United States; United States Food and Drug Administration

Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development.. This review briefly discusses the mechanisms of action and clinical applications of pazopanib . It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC.. Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Evaluation; Drug Monitoring; Humans; Indazoles; Kidney Neoplasms; Neoplasm Proteins; Pharmacovigilance; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; Sulfonamides; Up-Regulation; Vascular Endothelial Growth Factor A

Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC. The primary mechanism of action of pazopanib in RCC is through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of vascular endothelial growth factor receptor and platelet-derived growth factor receptor. A placebo-controlled phase III study demonstrated that pazopanib significantly improved response rates and progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients. Among treatment-naïve patients, the response rate was 32% and PFS was 11.1 months. In cytokine-pretreated patients, the response rate and PFS were 29% and 7.4 months, respectively. Common adverse effects of pazopanib include diarrhoea, hypertension and elevation of liver enzymes. Overall, the adverse effect profile of pazopanib is similar to that of other TKIs used for the treatment of RCC, but variation in the incidence and severity may exist. Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. Hepatic function must be monitored closely with dose interruption and/or reduction if elevation of hepatic function tests occurs. Pazopanib is administered on an empty stomach at a dose of 800 mg daily until disease progression, but dose reduction may be required in patients with baseline elevation of hepatic function tests, particularly total bilirubin. The minimum dose recommended for baseline hepatic dysfunction or toxicity is 200 mg daily. The potential for drug interactions exists for pazopanib. It is a substrate of cytochrome P450 (CYP) 3A4, P-glycoprotein and breast cancer resistance protein, and it weakly inhibits CYP3A4, CYP2C8 and CYP2D6, and potently inhibits UGT1A1 and OATP1B1. Currently, no study has directly compared pazopanib with other first- or second-line therapies in RCC. However, published clinical trials of pazopanib show similar efficacy outcomes to those of other targeted therapies. Therefore, pazopanib may be considered a first-line treatment option among other therapies including sunitinib, temsirolimus, and bevacizumab plus interferon-α. After failure of cytokine therapy, pazopanib is a treatment option as well as sorafenib or bevacizumab. No study has evaluated pazopanib treatment after failure of another targeted the

Topics: Animals; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Treatment Outcome

Therapeutic options in advanced renal-cell cancer have expanded through better understanding of molecular pathology and development of novel targeted therapeutics. Vascular endothelial growth factor, the key ligand of angiogenesis, has a major role in the progression of vascularized kidney tumors and this is the target molecule of modern medications. The three types of the mechanism of action of current therapies are: monoclonal antibodies blocking directly vascular endothelial growth factor ligand (bevacizumab), tyrosine-kinase inhibitors blocking vascular endothelial growth factor receptors (sorafenib, sunitinib, pazopanib) and inhibitors of the intracellular mTOR-kinase (temsirolimus, everolimus). Based on randomized studies, sunitinib, pazopanib or interferon-α-bevacizumab combination should be the first-line therapy in patients with good/moderate prognosis, while temsirolimus is recommended in those with poor prognosis. Following an ineffective cytokine therapy sorafenib or pazopanib are the second-line treatment. In case of tyrosine-kinase inhibitor inefficacy, current evidence favors everolimus. Patient outcome can further be improved by the involvement of more modern and effective target products.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.. This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.. The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents - sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) - have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Female; Humans; Indazoles; Kidney Neoplasms; Male; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Sulfonamides

The median survival of patients with metastatic renal cell carcinoma (mRCC) increased from 10 to more than 40 months since the advent of targeted therapy. The transformation of mRCC from an initially lethal disease to a more favorable entity, albeit incurable, occurred with the transition from best supportive care, to cytokines, to finally sequential targeted therapies. Sunitinib and bevacizumab (level 1b) represent the first-line standard of care for patients with clear-cell mRCC vs temsirolimus (level 2) for those with high-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with nonclear-cell mRCC histological subtypes. In second-line, everolimus proved its efficacy (level 1b). Nonetheless, sunitinib and sorafenib are also effective for nonclear-cell histological subtypes and after failure of other first-line treatment. The PFS benefits of first- and subsequent treatment-lines were confirmed in virtually all subgroup analyses. Potential survival benefits can be derived from cytoreductive nephrectomy (CNT), as was shown for cytokines in the general population, in sunitinib and bevacizumab-exposed patients. Phase III studies are ongoing to address the importance of CNT. This information is crucial to ensure timely delivery of a combination of medical and surgical therapies in this patient population.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Immunotherapy; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Neoplasm Metastasis; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Randomized controlled trials (RCTs) of multikinase inhibitors sunitinib, sorafenib, and pazopanib have reported efficacy compared with results from placebo and interferon-α (INF-α). To date, these drugs have not been compared in head-to-head trials.. To review systematically the evidence of clinical effectiveness of multikinase inhibitors in the treatment of metastatic renal cell carcinoma (mRCC) and, via an indirect meta-analysis, to determine an optimal treatment among these agents.. A systematic literature search of MEDLINE, EMBASE, CANCERLIT, and Cochrane controlled trials register databases was performed. All RCTs of multikinase inhibitors (sorafenib, sunitinib, and pazopanib) used to treat mRCC were included. The study selection, data extraction, and quality assessment were performed independently by 2 reviewers, with all disagreements being resolved by consensus. The effects of multikinase inhibitors on progression-free survival (PFS) were compared using an indirect treatment comparison method with INF-α or placebo as a comparator.. Four studies were included. Two studies examined sunitinib or sorafenib versus IFN-α, and the other 2 studies investigated sorafenib or pazopanib versus placebo. Compared with placebo, 2 interventions reported improvement for PFS (sorafenib: hazard ratio [HR] = 0.44, P = 0.01; pazopanib: HR = 0.46, P = 0.0001), whereas only sunitinib improved PFS over IFN-α (HR = 0.539, P = 0.001). An indirect comparison suggests that sunitinib is likely to demonstrate greater clinical benefit than sorafenib in terms of PFS (HR = 0.47; 95% CI, 0.316-0.713; P < 0.001), using IFN-α as the comparator. Sorafenib was not statistically different from pazopanib using placebo as the comparator in the indirect comparison (HR = 0.957; 95% CI, 0.657-1.39; P = 0.24).. Some multikinase inhibitors have a favorably reported PFS for patients with mRCC compared with results using IFN-α or placebo. Our findings suggest that sunitinib might offer some clinical benefit over sorafenib in terms of PFS. No statistical difference was found between sorafenib and pazopanib treatments. However, these conclusions are based on 2 indirect comparisons of single RCTs. More RCTs are required to confirm these findings and investigate the clinical effectiveness of multikinase inhibitors in the treatment of mRCC.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib

Insights into the biology of clear-cell renal cell carcinoma (CCRCC) have identified multiple pathways associated with the pathogenesis and progression of this cancer. This progress has led to the development of multiple agents targeting these pathways, including the tyrosine kinase inhibitors sorafenib, sunitinib, and pazopanib, the monoclonal antibody bevacizumab, and the mTOR inhibitors temsirolimus and everolimus. With the exception of temsirolimus, phase 3 trials tested these agents in patients with clear-cell histology; therefore, their efficacy in non-CCRCC is unclear. To date, there is no established effective therapy for patients with advanced non-CCRCC. This article focuses on treatment options for metastatic non-CCRCC.

Topics: Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

The perspectives of renal cell carcinoma (RCC) treatment have improved with the development of targeted molecular therapies against VEGFR/VEGF-mediated angiogenesis and mTOR. Antiangiogenic drugs, including bevacizumab (in association with IFN-α), sorafenib, sunitinib and pazopanib have demonstrated benefits for patients in terms of life expectancy, with progression free survival and overall survival exceeding 10 and 24 months, respectively. Long-term administration of these drugs, over several months or several years, requires the compliance of patients. Phase II/III studies on antiangiogenic-based therapy in RCC showed a high prevalence of fatigue (20 to 56%), whatever the drug assessed, but with the lowest rates observed with sorafenib or pazopanib. Fatigue is considered by cancer patients as the most important secondary effect regarding the impact on their quality of life and, consequently, is expected to compromise the protocol and the efficacy of the treatment. Management of fatigue induced by therapy or the disease is based on patient information, identification and treatment of causal aetiologies, anti-inflammatory therapy when needed and education and psychological support. Anticipating the risk and level of fatigue expected to be associated with cancer therapy by using both reliable and simple tools remains a challenge in oncology practice. The expected overall benefits of these targeted therapies, coupled with daily assessment and management of fatigue induced by the disease or the treatment, will offer new perspectives for patients with RCC. In this purpose, studies in oncology on the reliability of simple tools based on patient reporting and adapted to clinical practice, as well as interventional studies on fatigue management are needed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Fatigue; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sorafenib; Sulfonamides; Sunitinib

Renal cell cancer is the most common form of all malignant renal cancers. The most important exogenic risk factors are smoking and obesity. Most presentations are incidental and, when systemic symptoms occur they are often due to metastases. The mortality rate is still 30% in this disease. The only curative treatment option is surgery. Until recently interferon alpha and/or interleukin-2 were standard treatments in the palliative setting, but efficacy was limited. But in the last years advances could be made. Targeted therapies like sunitinib could demonstrate a significant improvement in progression free survival. Moreover, there are now treatment options even in second line palliative treatment. Nevertheless there are still enough questions to be answered: the optimal sequential therapy, how long should we treat our patients and can we combine theses targeted therapies? Studies to answer all these burning questions are already ongoing.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Evidence-Based Medicine; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Nephrectomy; Niacinamide; Palliative Care; Phenylurea Compounds; Practice Guidelines as Topic; Prognosis; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib

On June 14, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union for pazopanib for the treatment of advanced renal cell carcinoma. Pazopanib is an antineoplastic agent that inhibits multiple receptor tyrosine kinases. The recommended oral dose is 800 mg once daily. The benefit of pazopanib is an increased progression-free survival. In the pivotal trial VEG105192, the median progression-free survival was 9.2 months (95% confidence interval, 7.4-12.9) in the pazopanib arm compared with 4.2 months (95% confidence interval, 2.8-4.2) in the placebo arm. The most common side effects include diarrhea, hair color change, hypertension, nausea, fatigue, anorexia, vomiting, dysgeusia, elevated alanine aminotransferase, elevated aspartate aminotransferase, and abdominal pain. The objective of this article is to summarize the scientific review of the application that led to approval in the European Union.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Renal cell carcinoma accounts for 2-3% of all adult malignancies worldwide, and around 30% of patients with the condition present with advanced or metastatic disease.1,2 Until recently, cytokine therapy (e.g. interleukin-2 or interferon-alfa) was the standard treatment for metastatic renal cell carcinoma but provided only a small survival advantage (e.g. extending life by a median of 2.5 months).3 A key development has been the introduction of drugs known as receptor tyrosine kinase inhibitors, which include ▾sunitinib (Sutent-Pfizer), ▾sorafenib (Nexavar-Bayer) and ▾pazopanib (Votrient-GlaxoSmithKline). Here we review the evidence on the efficacy, tolerability and cost-effectiveness of these treatments in renal cell carcinoma.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Drug Costs; Humans; Indazoles; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Practice Guidelines as Topic; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, responsible for approximately 90% of all kidney cancers. Prior to 2005, treatment options for patients with locally advanced and metastatic disease were limited. After the approval of sorafenib by the US Food and Drug Administration (FDA), other tyrosine kinase inhibitors (TKI) have been successively used for treating patients with advanced RCC. Pazopanib is the newest, orally bioavailable, and multi-targeted TKI, and is considered a first-line treatment option for certain patients. This review summarizes updated clinical studies, mechanism of action, and pharmacokinetics of pazopanib.. Published English language literatures and data information on pazopanib for treating advanced RCC available as of March 2011 were identified and summarized.. In phase II and III randomized clinical trials, pazopanib treatment resulted in considerably longer progression-free survival in patients with advanced RCC compared to placebo, with an acceptable side-effect profile. In addition, there are a few ongoing pazopanib studies including comparison to other TKIs, use for patients who have failed prior cytokine therapy, and combination with other therapeutic agents.. Pazopanib has been used in the United States, Europe and Canada for treating patients with advanced RCC. Currently, it is being used in good or intermediate risk RCC and shows survival benefit with acceptable adverse effects. Pazopanib is a new treatment option and needs further evaluation, particularly on its effect relative to other TKIs as well as its use in combination with other agents.

Topics: Administration, Oral; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Humans; Indazoles; Kidney Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides; Treatment Outcome

To summarize the currently available clinical data on pazopanib, as well as review the merits and adverse effects of pazopanib in the treatment of renal cell carcinoma (RCC).. A literature search was performed of MEDLINE, PubMed, and the American Society of Clinical Oncology abstracts from January 1995 to February 2010, using the primary search terms pazopanib, GW786034, Votrient, and tyrosine kinase inhibitors.. All available English-language articles and trials that described the pharmacokinetics, pharmacology, pharmacodynamics, clinical activity, or adverse effects of pazopanib were reviewed.. Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor (TKI) that has exhibited antiangiogenic and antitumor activity. Phase 1 clinical trials have established the safety and tolerability of pazopanib 800 mg orally daily. Phase 2 and 3 studies have shown promising activity in RCC, including treatment naïve or cytokine-pretreated patients, demonstrating a greater rate of total disease control with pazopanib compared to placebo. Activity has also been shown in a variety of other cancers, including ovarian cancer, non-small-cell lung cancer, breast cancer, and soft tissue sarcoma. The most common adverse effects of pazopanib include nausea, diarrhea, hypertension, hair depigmentation, and elevated transaminase levels. Adverse effects are most commonly Grades 1-2. Other Phase 3 trials are ongoing in RCC, including a comparison to sunitinib, another TKI used in RCC, as well as trials in other tumor types.. Current data suggest pazopanib to be a viable treatment option as first-line therapy for advanced RCC. Data are awaited comparing pazopanib to other TKIs. Until results of head-to-head trials conducted of the various agents are available, it cannot be said whether pazopanib is more tolerable or efficacious than currently available therapies.

Topics: Administration, Oral; Animals; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Delivery Systems; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides

Treatment options for patients with metastatic renal cell carcinoma (RCC) have changed dramatically, and a new paradigm has evolved. IFN-alpha and IL-2 were previously mainstays of therapy, but since December 2005, six new agents have been approved in the USA for the treatment of advanced RCC. Three of these new agents are multitargeted kinase inhibitors, including sunitinib, sorafenib, and recently pazopanib, two target the mTOR (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with IFN-alpha) that targets VEGF. Sunitinib has emerged as the standard of care for treatment-naive RCC patients, with the recently approved bevacizumab and IFN-alpha combination providing an additional option for this population. The recent approval of pazopanib, based on the results from sequential Phase II and III clinical trials demonstrating improved overall response rates and progression-free survival, provides yet another option for front-line therapy. The current article examines the pazopanib preclinical and clinical data, provides an overview of the development of this tyrosine kinase inhibitor, and provides some speculation concerning its role in RCC therapy.

Topics: Animals; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sulfonamides

Pazopanib is an orally administered, multi-tyrosine kinase inhibitor that interrupts tumor growth in renal cell carcinoma. In a randomized, double-blind, placebo-controlled, multinational trial in patients with locally advanced or metastatic renal cell carcinoma, the median progression-free survival (PFS) of patients who were treated with pazopanib 800 mg once daily was significantly longer than that of placebo recipients (9.2 vs 4.2 months; hazard ratio 0.46 [95% CI 0.34, 0.62]). In prespecified analyses in treatment-naive and cytokine-pretreated patients, grouped according to prior treatment history, age, sex, Memorial Sloan-Kettering Cancer Center risk category, and Eastern Cooperative Oncology Group performance status, median PFS was significantly longer in pazopanib than placebo recipients in all subgroups. Pazopanib recipients also had a significantly higher overall response rate than placebo recipients; in pazopanib recipients, the median time to response was 11.9 weeks and the median duration of response was 58.7 weeks. Oral pazopanib had an acceptable tolerability profile in patients with advanced renal cell carcinoma. Adverse events were common in pazopanib and placebo recipients and were mostly of mild to moderate severity.

Topics: Anticarcinogenic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Progression; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides

Pazopanib is an oral, multitargeted tyrosine kinase inhibitor that has been approved by the U.S. Food and Drug Administration for treatment of patients with advanced renal cell cancer on the basis of a randomized, double-blind, placebo-controlled, phase III trial, which showed that once a day dosing of 800 mg of pazopanib resulted in progression free survival of 9.2 months versus 4.2 months (P < 0.0001). Pazopanib thus joins sorafenib and sunitinib as one of the clinically available VEGF receptor (VEGFR)-targeted drugs for the treatment of patients with advanced clear cell renal cell cancer. The mechanism of action, preclinical and clinical data, and a comparison with the other drugs in its class are outlined below.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Over the last few years, targeted agents have assumed a predominant role in treatment of metastatic renal cell carcinoma (mRCC). Our aim is to discuss recent developments on this rapidly evolving topic.. Sunitinib represents front-line standard treatment for the good- and intermediate prognosis groups of patients with clear cell renal carcinoma. Bevacizumab/interferon and pazopanib have also been FDA-approved as first-line agents, while sorafenib has moved toward second-line and later therapy. Temsirolimus, an mTOR inhibitor, is recommended as front line therapy for patients in the poor-risk group and is the best front-line choice for patients with non-clear cell histology. Another mTOR inhibitor, everolimus, has shown clinical benefit post-tyrosine kinasis inhibitors failure in a phase III study and is considered the standard of care in this setting. Novel prognostic and efficacy markers might help to define most appropriate therapeutic strategy. Best sequence of use of these effective agents in mRCC patients remains up to the discretion of treating physician.. In light of the considerable advances in understanding the biology of mRCC, several new drugs have been recently developed, with an increasing number of treatment options. Several markers are under evaluation for diagnostic, prognostic and efficacy purposes. A treatment algorithm, based on the best scientific evidence produce so far, is presented and it will evolve as data from ongoing trials will be available.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Immunotherapy; Indazoles; Interferons; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides; TOR Serine-Threonine Kinases

Recent advances in understanding the fundamental biology underlying clear-cell RCC have opened the door to a series of targeted agents, such as tyrosine kinase inhibitors (TKIs) or mTOR inhibitors. These new agents have become the standard of care in managing advanced clear-cell RCC. Choice of initial medical management in patients with metastatic clear-cell RCC should be guided by randomised studies. On the evidence available, the first-line therapy in patients with good- or intermediate-risk mRCC should be either sunitinib or pazopanib, or bevacizumab plus interferon. In selected patients sorafenib is an option, as is high-dose interleukin-2 if performance status is good. In patients with poor prognosis, temsirolimus is recommended. In cytokine refractory patients, sorafenib, when patients have progressed on a tyrosine kinase inhibitor everolimus is the agent of choice. Biró K, Küronya Z. Recent advancements in the treatment of renal cell carcinoma - focus on international guidelines.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Europe; Humans; Immunotherapy; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The development of targeted molecules in renal carcinogenesis changed the therapeutic approaches of treatment for metastatic clear cell renal cell carcinoma. Four available drugs are currently available, i.e. bevacizumab, sunitinib, sorafenib and temsirolimus, but other molecules and combined therapy are under investigation. In this review we assess published reports of these targeted therapies and discuss the novel promising molecules targeting vascular endothelial growth factor and its receptors, the mammalian target of rapamycin and epithelial growth factor cascade.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factors

Inactivation of the von Hippel-Lindau tumor suppressor gene in most sporadic renal cell carcinoma (RCC) tumors leads to a fundamental reliance on elements of this pathway, namely, the potent proangiogenic factor, vascular endothelial growth factor (VEGF). Thus, VEGF-targeted therapeutics have undergone extensive clinical testing in RCC. Approaches to bind circulating VEGF protein (eg, bevacizumab) and small molecule inhibitors of the receptor on which the VEGF ligand binds (eg, sunitinib, sorafenib, axitinib, and pazopanib) have been tested. Robust clinical effects have been observed, including high objective response rates, prolonged progression-free survival, and evidence of long overall survival for patients with metastatic RCC patients who are treated with these agents. Future directions include investigation of combination and sequenced therapy, elucidation of mechanisms of response and resistance, and exploration of the effect of these agents in other disease settings.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Pazopanib (Votrient, GW786034) is a potent pan-VEGF inhibitor in advanced clinical development. Like other orally available VEGFR inhibitors, pazopanib is clinically efficacious and well tolerated. The recently reported Phase III clinical trial in metastatic renal cell carcinoma showed activity similar to approved agents with variations in toxicity which has led to its recent FDA approval. Given the growing number of agents in this category, differences not only in single-agent activity but also toxicity and combinatorial potency will probably distinguish pazopanib from other similar agents.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Indazoles; Kidney Neoplasms; Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Vascular Endothelial Growth Factors

Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR1, -2 and -3, PDGFRalpha, PDGFRbeta and c-Kit. Preclinical evaluation has revealed excellent anti-angiogenic and antitumor activity in several tumors. A phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab-pretreated renal cell carcinoma (RCC) has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled phase III trial in untreated or cytokine-treated patients with RCC demonstrated a significant improvement in progression-free survival. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Indazoles; Kidney Neoplasms; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides

Treatment of advanced renal cell carcinoma (RCC) has undergone significant changes over the past 3 years after a long period of relative stagnation. A better understanding of the biology of the tumor led to the discovery of molecular targeted therapies resulting in significant improvement in outcome for this common malignancy.. A review of new drugs, both established and investigational, at present used in the treatment of RCC is provided in this article.. A comprehensive free-text search of all available published literature including but not limited to, Medline, Scopus, American Society of Clinical Oncology presentations, National Comprehensive Cancer Network guidelines and information available through other national and international scientific organizations was carried out during the preparation of this manuscript.. Targeted therapy in RCC is a prime example of successful translational research. Continuing clinical and preclinical research in drug development holds promise for further advances in this area.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-kit.. Data supporting the development of pazopanib for RCC are reviewed.. Preclinical and clinical data available for pazopanib are presented.. Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides

Recent developments in the understanding of the molecular biology of renal cell carcinoma have led to the development of several biologic agents with different mechanisms of action. In 2005, promising results have been observed especially in second-line therapy following cytokine failures and in 2006 more mature data with regard to time to progression and overall survival should be available. This review, analyzing basic translational research principles, will summarize the available evidence with a glimpse of the future therapeutic approaches in renal cell carcinoma.. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs (SU11248, Bay 43-9006, Bevacizumab, AG-013736, etc.) report time to progression ranging between 4 and 9 months and variable benefits in overall survival. Confirmatory studies are ongoing regarding other novel treatments (CCI-779, Infliximab, PTK-787).. In renal cell carcinoma, there is a strong rationale for targeting multiple pathways and particularly angiogenesis. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs have been rapidly approved in the second-line setting and will soon be used as first-line therapy. In the next years, translational/clinical research will provide evidence for combination strategies to improve upon the results of the biologic agents and hopefully offer more hope to patients with renal cell carcinoma.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Erlotinib Hydrochloride; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response.. This was a phase I to II trial on the combination of pazopanib with interferon-alpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease.. Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of follow-up, 24 (72.7%) patients were still alive. CCL2, IL8, TNF-α, and PD-L1 were significantly overexpressed after treatment initiation, while TGF-β1 and CCL5 were significantly decreased. TNF-α, endoglin, and PD-L1 expression are correlated with the response after treatment initiation.. The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A.

Topics: B7-H1 Antigen; Biomarkers; Carcinoma, Renal Cell; Humans; Indazoles; Interferon-alpha; Kidney Neoplasms; Prognosis; Pyrimidines; Sulfonamides; Treatment Outcome; Tumor Necrosis Factor-alpha

Patients with advanced renal cell carcinoma and poor performance status (PS≥2) are often deemed unsuitable for treatment. The Pazo2 trial aimed to assess tolerability and efficacy of pazopanib as first-line treatment in renal cancer patients with ECOG PS2.. Pazo2 was a prospective, single arm, open label, multicentre, phase II trial, conducted in 26 UK centres. Eligible patients were aged ≥18 years, with advanced or metastatic renal cancer and a clear cell component (aRCC), measurable disease as per RECIST Criteria 1.1, and ECOG PS2. Co-primary outcomes, assessed at 6-months after patients entered the trial, were tolerability, defined as the proportion of patients who did not develop "intolerable" adverse events, and efficacy, defined as the proportion of all patients who were progression-free and alive.. Between February 21, 2013 and August 12, 2016, 75 patients were registered. Median age was 68.6 years (IQR 64.6-76.0), 100% ECOG PS2, 62.7% 'poor risk' (International Metastatic Renal-Cell Carcinoma Database Consortium). Of the 65 evaluable patients, 70.8% (95% CI: 58.8, 80.4) did not develop "intolerable" adverse events and 56.9% (95% CI: 44.8, 68.2) were still alive and progression-free 6 months after starting pazopanib. Twenty-seven patients developed serious adverse events deemed to be related to pazopanib.. These data suggests that pazopanib is tolerated and effective in aRCC patients with PS2 and represents a treatment option for patients who cannot receive or tolerate immune checkpoint inhibitors.

Topics: Adolescent; Adult; Aged; Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Indazoles; Kidney Neoplasms; Prospective Studies; Pyrimidines; Sulfonamides

Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking.. PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI).. Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48-11.83). 19% of patients (21/109) were long-term responders (on pazopanib for ≥18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%).. Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies.

Topics: Adult; Africa, Northern; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Asia; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Middle East; Progression-Free Survival; Prospective Studies; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Risk Factors; Sulfonamides; Time Factors; Treatment Outcome; Young Adult

Pazopanib is an oral angiogenesis tyrosine kinase inhibitor (TKI) recommended in metastatic renal cell carcinoma (mRCC) for treatment-naïve patients or those experiencing cytokine failure. We conducted a phase 2, open-label, single-arm study in ten Spanish centres among mRCC patients whose disease progressed on first-line TKI. Patients received pazopanib until disease progression, death, or unacceptable toxicity. Twenty-seven patients were included (median age 62yr, 51.9% male). The objective overall response rate was 14.8% (95% confidence interval [CI] 1.4-28.2%). Median progression-free survival was 6.7mo (95% CI 3.7-11.2) and median overall survival was 20.6mo (95% CI 12.6-27.4). Lower circulating levels of IL-10 (p=0.002) were observed in responding patients at 8 wk after treatment. The median pazopanib treatment duration was 6.0mo (range 1.0-47.0). Most patients (48.1%) had mild or moderate adverse events (AEs), while 44.4% had severe AEs. Pazopanib was clinically active and well tolerated as a second-line treatment in mRCC patients after TKI failure, and circulating IL-10 levels could predict response. PATIENT SUMMARY: Pazopanib could be used as a second-line therapy for the treatment of metastatic renal cell carcinoma after failure of tyrosine kinase inhibitor (TKI) therapy when drugs such as nivolumab and cabozantinib are not available. Now that immunotherapy plus antiangiogenic therapy is a first-line option, IL-10 levels deserve further exploration as a potential predictor of response to sequential TKI-TKI therapy.

Topics: Biomarkers; Carcinoma, Renal Cell; Female; Humans; Immunotherapy; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Diarrhea; Fatigue; Female; Humans; Hypothyroidism; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Nausea; Neoplasm Metastasis; Pyrimidines; Sulfonamides; Treatment Outcome

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66-84; placebo, 77 mo, IQR 69-85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80-1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m

Topics: Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Neoplasm Recurrence, Local; Nephrectomy; Pyrimidines; Sulfonamides

Fatigue is one of the most common adverse events of systemic therapy in patients with metastatic renal cell carcinoma (RCC). The aim of multicenter randomized phase 2 study was to determine the efficacy and safety of testosterone in patients with fatigue developed during targeted therapy.. Male patients with metastatic clear-cell RCC, normal prostate-specific antigen level, low testosterone level, and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either testosterone undecanoate (1000 mg) and targeted therapy or targeted therapy alone. The primary endpoint was the mean change of fatigue from baseline to 28 days according to the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary endpoints were safety, Functional Assessment of Cancer Therapy-Kidney Symptom Index 19, testosterone serum concentrations, red blood cell count, and hemoglobin level.. Sixty patients were assigned to receive testosterone and targeted therapy (N=30) or targeted therapy alone (N=30). As of the data cutoff on December 30, 2019, median follow-up was 18.2 months. The study achieved its primary endpoint based on the significant differences at day 28 favoring testosterone over targeted therapy alone regarding the decreased level of fatigue (difference between groups, 22.5 points; 95% confidence interval, 18.4-26.6; P=0.012). Significant changes in scores demonstrating the enhanced quality of life with testosterone compared with targeted therapy were also observed for Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 disease-related symptoms (P=0.01). There were nonsignificant differences in red blood cell count and hemoglobin level between the 2 groups (all P>0.05).. Male patients with metastatic RCC and hypogonadism receiving testosterone had less fatigue and better symptom control during targeted therapy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Fatigue; Follow-Up Studies; Humans; Hypogonadism; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Quality of Life; Sulfonamides; Sunitinib; Testosterone

Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Indazoles; Interleukin-10; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Polyethylene Glycols; Pyrimidines; Sulfonamides; Survival Analysis; Treatment Outcome; Young Adult

This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma.. This was an open-label, two-part, multicenter study involving treatment-naïve patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted.. Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group.. Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome

Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment.. To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib.. SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive.. Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events.. Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Prospective Studies; Pyrimidines; Sulfonamides; Sunitinib; Treatment Failure; Treatment Outcome

Pazopanib is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and soft-tissue sarcoma. At the approved dose of 800 mg once daily (QD), 16-20% of patients are being underdosed and at risk of decreased efficacy. This study aimed to show whether splitting intake moments, as a cost-neutral alternative to a dose increase, leads to an increased exposure.. We performed a cross-over trial comparing the pharmacokinetics of pazopanib 800 mg QD with pazopanib 400 mg twice daily. Pharmacokinetic sampling was performed at steady-state for both dosing schedules.. This study demonstrates that splitting intake moments of pazopanib leads to a 79% increase in C. NL6137 ( http://www.trialregister.nl ).

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Prospective Studies; Pyrimidines; Sulfonamides

Accurate prediction of early treatment response to systemic therapy (ST) with tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (mRCC) could help avoid ineffective and expensive treatment with serious side effects. Neither RECIST v.1.1 nor Choi criteria successfully discriminate between patients with mRCC who received ST having a short or long time to progression (TTP). There is no biomarker, which is able to predict early therapeutic response to TKIs application in patients with mRCC. The goal of our study was to investigate the potential of apparent diffusion coefficient (ADC) of diffusion-weighted imaging (DWI) of MRI in prediction of early therapeutic response to ST with pazopanib in patients with mRCC. The retrospective study enrolled 32 adult patients with conventional mRCC who received pazopanib (mean duration-7.5 ± 3.45). The mean duration of follow-up was 11.85 ± 4.34 months. In all patients as baseline examination and 1 month after treatment, 1.5T MRI including DWI sequence was performed followed by ADC measurement of the main renal lesion. For assessment of the therapeutic response, RECIST 1.1 is used. Partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 12 (37.50%), 10 (31.25%) and 10 (31.25%) cases with mean TTP of 10.33 ± 2.06 months (95% confidence interval, CI = 9.05-11.61), 7.40 ± 2.50 months (95% CI = 5.61-9.19) and 4.20 ± 1.99 months (95% CI = 2.78-5.62) accordingly (p < 0.05). There was no difference in change of main lesions' longest size 1 month after ST in patients with PR, SD and PD. Comparison of mean ADC values before and 1 month after systemic treatment showed significant decrease by 19.11 ± 10.64% (95% CI = 12.35-25.87) and by 7.66 ± 6.72% (95% CI = 2.86-12.47) in subgroups with PR and SD, respectively (p < 0.05). There was shorter TTP in patients with mRCC if ADC of the main renal lesion 1 month after the ST increased from the baseline less than 1.73% compared to patients with ADC levels above this threshold: 5.29 ± 3.45 versus 9.50 ± 2.04 months accordingly (p < 0.001). Overall, our findings highlighted the use of ADC as a predictive biomarker for early therapeutic response assessment. Use of ADC will be effective and useful for reliable prediction of responders and non-responders to systemic treatment with pazopanib.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Diffusion Magnetic Resonance Imaging; Female; Healthy Volunteers; Humans; Indazoles; Kaplan-Meier Estimate; Kidney; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Retrospective Studies; ROC Curve; Sulfonamides; Treatment Outcome

We performed a pooled analysis of the COMPARZ study assessing efficacy and safety of pazopanib versus sunitinib in treatment-naïve Chinese patients with locally advanced and/or metastatic renal cell carcinoma (a/mRCC).. In the COMPARZ study, patients were randomized (1:1) to receive pazopanib 800 mg once daily (QD) continuously or sunitinib 50 mg QD in 6-week cycles (4 weeks on, 2 weeks off). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. PFS and ORR were assessed by independent review committee (IRC) and local investigators.. Of the 209 Chinese patients (pazopanib, [n = 109] and sunitinib, [n = 100]), 155 (74%) were males and median age was 57 years (range, 18-79). Median PFS was 13.9 months for pazopanib versus 14.3 months for sunitinib per investigator assessment and 8.3 months in both arms per IRC assessment; PFS hazard ratio was 1.17 (investigator) and 0.99 (IRC). Median OS was not reached in pazopanib arm and was 29.5 months in sunitinib arm. ORR was significantly higher in pazopanib arm versus sunitinib arm (investigator: 41% versus 23% [P = 0.0052]; IRC: 35% versus 20% [P = 0.0203]). Pazopanib was generally well tolerated in Chinese patients with a/mRCC. Most frequent AEs in the pazopanib arm were diarrhea and hair color changes whereas the most frequent AEs in the sunitinib arm were decreased platelets, decreased neutrophil count, and thrombocytopenia.. The results of the pooled analysis were consistent with the overall population in the COMPARZ study, and confirmed similar PFS and OS of pazopanib and sunitinib in the Chinese patients.. clinical trials.gov, NCT00720941 (August 14, 2008) and NCT01147822 (May 19, 2010).

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; China; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Pyrimidines; Sulfonamides; Sunitinib; Young Adult

BACKGROUNDSurgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%-40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODSccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTSTwenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSIONNeoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDINGSupport was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.

Topics: Adult; Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Renal Cell; Case-Control Studies; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Prognosis; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Rate; Transcriptome

Temsirolimus has level 1 evidence for initial treatment of poor-risk patients with advanced renal cell carcinoma (mRCC), but its efficacy has not been directly compared with an antiangiogenic tyrosine kinase inhibitor (vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKi]) in this setting.. To evaluate temsirolimus versus pazopanib as first-line therapy in patients with mRCC, predominant clear-cell features, and clinical characteristics of a poor prognosis.. A randomized (1:1) phase II trial in 69 treatment-naïve mRCC patients and with three or more predictors of short survival for temsirolimus was conducted during 2012-2017 in a single academic cancer center. Crossover to the alternative treatment upon discontinuation of the first-line agent was permitted.. Mechanistic target of rapamycin inhibitor temsirolimus and VEGFR TKi pazopanib.. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), safety, and patient-reported outcomes (PROs). Radiographic response was assessed by blinded radiologists. Efficacy outcomes were adjusted by prior nephrectomy status, prior interleukin-2 treatment, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score.. Thirty-five patients received temsirolimus and 34 received pazopanib upfront; 72% overall had poor risk by IMDC. Median PFS in the first line was 2.7mo with temsirolimus and 5.2mo with pazopanib (adjusted hazard ratio [HR] 1.36, 95% confidence interval [CI] 0.84-2.22; p=0.210). Median OS was 7.1mo with temsirolimus and 11.9mo with pazopanib (adjusted HR 1.16, 95% CI 0.70-1.93; p=0.558), and ORRs were 5.9% and 21.2%, respectively (adjusted odds ratio 5.2, 95% CI 0.9-29.3; p=0.062). PRO measures favored pazopanib. Five patients discontinued first-line therapy due to adverse events.. Temsirolimus and pazopanib had modest activity in patients with poor-risk clear-cell mRCC, and therefore their use should be discouraged in this setting.. We evaluated outcomes of advanced renal cell carcinoma patients presenting with aggressive features when treated with temsirolimus or pazopanib as first-line therapy. Survival was <1yr for most, suggesting that more efficacious alternative treatments should be favored for these patients.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Pyrimidines; Risk Assessment; Single-Blind Method; Sirolimus; Sulfonamides

The phase III COMPARZ study showed noninferior efficacy of pazopanib versus sunitinib in advanced renal cell carcinoma. In this COMPARZ post hoc analysis we characterized pazopanib responders, patient subgroups with better outcomes, and the effect of dose modification on efficacy and safety.. Patients were randomized to pazopanib 800 mg/d (n = 557) or sunitinib 50 mg/d, 4 weeks on/2 weeks off (n = 553). Secondary end points included time to complete response (CR)/partial response (PR); the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days.. Median time to response was numerically shorter for patients treated with pazopanib versus sunitinib (11.9 vs. 17.4 weeks). Similar percentages of pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). For patients without versus with adverse event (AE)-related dose reductions, median PFS, median overall survival, and ORR were 7.3 versus 12.5 months, 21.7 versus 36.8 months, and 22% versus 42% (all P < .0001) for pazopanib, and 5.5 versus 13.8 months, 18.1 versus 38.0 months, and 16% versus 34% (all P < .0001) for sunitinib; results were similar for dose interruptions.. Dose modifications when required because of AEs were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients.

Topics: Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Indazoles; Kidney Neoplasms; Logistic Models; Male; Pyrimidines; Random Allocation; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment.. A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied.. 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS.. In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations.. ClinicalTrials.gov: NCT01264341.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Background Pazopanib is approved for metastatic renal cell carcinoma (RCC). We assessed the safety and efficacy of pazopanib with a low fat meal (LFM): <400 cal and < 20% fat or 10 g per meal. Methods A single arm study of pazopanib with a LFM in 16 adult patients with metastatic RCC with a clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤ 2, and ≤ 3 prior therapies. Pazopanib at 400 mg daily given with LFM for 12 weeks. Incremental dose increases up to 800 mg, or irreversible decreases to 200 mg, allowed every 2 weeks. Primary study endpoint was safety; adverse events (AE) measured per CTCAE version 4.0. Secondary endpoints of RECIST 1.1 response with assessment as 12 weeks; pharmacokinetic (PK) analysis at nine time points, and CYP3A4 polymorphism evaluation. Results Pazopanib with a LFM was well tolerated; 13 of 16 subjects completed all 12 weeks. Three patients withdrew due to adverse events (AEs), with five occurrences of grade 3 AEs. Conclusions Pazopanib with a LFM has acceptable safety and comparable efficacy to fasting administration. Total median pazopanib dose per subject for the study duration was 63.5% of maximum possible conventional dose. A larger study is warranted. Clinical Trial Registration Number: NCT02729194.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Combined Modality Therapy; Diet, Fat-Restricted; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Prognosis; Pyrimidines; Sulfonamides

This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versa in advanced/metastatic renal cell carcinoma (mRCC) patients.. This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety.. A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension.. Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence.. NCT01613846, www.clinicaltrials.gov.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Patient Safety; Prognosis; Pyrimidines; Sorafenib; Sulfonamides; Survival Rate; Young Adult

Pazopanib is an effective treatment option for renal cell carcinoma (RCC). However, the therapy is often limited by the appearance of adverse events (AEs), including nausea/vomiting, hepatic impairment, hand-foot syndrome, diarrhea, hypertension and oral mucositis. Early management of AEs is, therefore, extremely important in order to maximize treatment outcomes.. This non-randomized controlled before-and-after study was carried out to evaluate the effectiveness of our comprehensive pharmaceutical interventions in 37 outpatients receiving pazopanib for RCC (experimental group). Data were compared with those obtained from 13 patients before the start of pharmaceutical intervention (control group).. The incidence rates of grade 2 or more nausea and anorexia were significantly lower in the experimental, than in the control group (3% versus 38% for nausea, respectively, p=0.003; 8% versus 46% for anorexia, respectively, p=0.005). Importantly, non-adherence based on patient self-assessment was not observed with intervention (0% versus 38%, p<0.001). Consequently, the median total dose of pazopanib was increased by the intervention (72,600 versus 18,200 mg, p=0.002). Moreover, the median time to treatment failure was significantly longer with intervention than before (10.2 versus 1.7 months, HR=0.23, 95% CI=0.110-0.499, p<0.001). These findings suggest that our interventions are highly effective for enhancing treatment outcomes.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Female; Humans; Incidence; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Medication Adherence; Middle Aged; Neoplasm Metastasis; Outpatients; Patient Compliance; Pyrimidines; Self Report; Sulfonamides; Treatment Outcome

Two main therapies, pazopanib and sunitinib, are used in the first-line setting for metastatic renal cell carcinoma (mRCC). These two tyrosine kinase inhibitors (TKI) are equally effective in terms of survival; however, they frequently induce adverse events. In this setting, Health-Related Quality of life (HRQoL) is a key element in the choice between these two treatments and the evaluation of treatment effectiveness. It could be of interest to evaluate HRQoL in daily clinical practice to aid adequate therapy choice and management. Currently, the development of information and communication technology may allow HRQoL monitoring in routine practice. The objective of the QUANARIE study is to evaluate the use of HRQoL assessment in daily clinical practice for patients with mRCC treated with TKI using electronic patient-reported outcomes (e-PRO). The present article describes the key elements of the study protocol.. The QUANARIE study is an interventional, prospective, multicentre trial. Patients diagnosed with mRCC initiating sunitinib or pazopanib treatment will be invited to complete the EORTC QLQ-C30 questionnaire, nine additional questions from the EORTC items library, and the EuroQoL EQ-5D, prior to each visit with the physician. Questionnaires will be completed by patients using tablets and/or computer terminals via the e-PRO software. The physician will have real-time access to a visual summary of the HRQoL evaluation. The primary objective is to assess the proportion of patients having good compliance with Routine Electronic Monitoring of HRQoL (REMOQOL) during the first 12 months. Physicians' satisfaction with REMOQOL will be assessed as a secondary objective. We hypothesise that 80% of patients having good compliance with REMOQOL would be meaningful. A sample size of 56 patients would be needed.. The results of this study will show whether REMOQOL is feasible on a large scale and whether patients are receptive to this new practice. This study will also determine how real-time multidimensional evaluation of patient perception can help physicians in their daily practice and how they used it in conjunction with other clinical information to manage patient care.. ClinicalTrials.gov; Identifier: NCT03062410 ; First Posted: February 23, 2017; Last Update Posted: August 9, 2017.

Topics: Adult; Aged; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Patient Reported Outcome Measures; Prospective Studies; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Quality of Life; Sulfonamides; Sunitinib; Surveys and Questionnaires; Treatment Outcome; Young Adult

The optimal treatment strategy for patients with metastatic non-clear cell type renal cell carcinoma (nccRCC) remains unclear. Although several inhibitors of vascular endothelial growth factor have recently shown efficacy against nccRCC, the clinical benefit of pazopanib in nccRCC has not been analyzed. We therefore designed a single-arm, open-label, phase II study to determine the efficacy and safety of pazopanib in patients with nccRCC.. Patientswith locally advanced or metastatic nccRCC, exceptfor collecting duct or sarcomatoid type, received 800 mg/day of pazopanib daily until progression of disease or intolerable toxicity. One cyclewas defined as 4weeks and tumorresponsewas evaluated every two cycles. The primary objective was overall response rate (ORR).. A total of 29 eligible patients were enrolled at nine centers in Korea from December 2012 and September 2014. The median age of the patients was 58 years (range, 27 to 76 years) and 21 patients (72%) were male. Regarding histology type, 19 patients had papillary, three had chromophobe, two had unclassified and five had unknown non-clear cell type. Of 28 evaluable patients, eight achieved a confirmed partial response with ORR of 28%. The median progression-free survival was 16.5 months (95% confidence interval, 10.9 to 22.1) and median overall survival was not reached. Sixteen patients (55%) experienced treatment-related toxicity of grade 3 or more, but most adverse events were overcome through dose reduction and delay.. In this prospective phase II study, pazopanib demonstrated promising activity and tolerable safety profile in patients with metastatic nccRCC.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Sulfonamides

Early tumor shrinkage (eTS) has prognostic value in metastatic renal cell carcinoma (mRCC). We aimed to validate the role of eTS in first line treatment from the COMPARZ study (NCT00720941).. 1100 patients treated with sunitinib or pazopanib were analyzed for tumor response according to RECIST 1.0. eTS was defined as tumor shrinkage by ≥ 10%. A landmark analysis was performed on day (d) 42 and 90 and Cox proportional hazards regression was computed for the prognostic effect of eTS.. In patients with eTS median OS was 34.1 [CI 95% 28.4; not reached (NR)] and 33.6 (CI 95% 30.1; NR) months (mo) at d 42 and 90, respectively, compared to 19.6 (CI 95% 14.0; 28.9) and 15.1 (CI 95% 12.4; 18.7) mo for patients without eTS. There was no interaction between type of treatment and eTS (d 42 p = 0.79; d 90 p = 0.37). eTS ≥ 10% remained an independent prognostic marker in multivariable analyses at both d 42 and 90.. Similar results were found for eTS at the 42 and 90 days landmarks. eTS ≥ 10% has prognostic relevance in mRCC and reflects a putative tool to guide future clinical treatment.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Pyrimidines; Regression Analysis; Response Evaluation Criteria in Solid Tumors; Sulfonamides; Sunitinib; Treatment Outcome; Tumor Burden

The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations.. Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off).. Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%).. A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations.. ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Carcinoma, Renal Cell; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Sulfonamides; Sunitinib; White People; Young Adult

In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC), after prior antiangiogenic therapy.. Outcomes were evaluated for subgroups defined by prior therapy with sunitinib or pazopanib as the only prior VEGFR inhibitor, or prior anti-PD-1/PD-L1 therapy.. For the prior sunitinib subgroup (N = 267), median PFS for cabozantinib versus everolimus was 9.1 versus 3.7 months (HR 0.43, 95% CI 0.32-0.59), ORR was 16% versus 3%, and median OS was 21.4 versus 16.5 months (HR 0.66, 95% CI 0.47-0.93). For the prior pazopanib subgroup (N = 171), median PFS for cabozantinib versus everolimus was 7.4 versus 5.1 months (HR 0.67, 95% CI 0.45-0.99), ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR 0.66, 95% CI 0.42-1.04). For prior anti-PD-1/PD-L1 therapy (N = 32), median PFS was not reached for cabozantinib versus 4.1 months for everolimus (HR 0.22, 95% CI 0.07-0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR 0.56, 95% CI 0.21-1.52).. Cabozantinib was associated with improved clinical outcomes versus everolimus in patients with advanced RCC, irrespective of prior therapy, including checkpoint inhibitor therapy.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anilides; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyridines; Pyrimidines; Sulfonamides; Sunitinib; Treatment Outcome

The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data.. A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective.. The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib.. When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Canada; Carcinoma, Renal Cell; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Indazoles; Kidney Neoplasms; Male; Markov Chains; Middle Aged; Pyrimidines; Quality-Adjusted Life Years; Sulfonamides; Sunitinib; Treatment Outcome

Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.. Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.. Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.. The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.. Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Pyrimidines; Sulfonamides; Sunitinib

The trial is approved by the Southeast London Research Ethics Committee reference 16/LO/1499 and registered on the NIHR clinical research network portfolio ISRCTN12114913 .

Topics: Adult; Aged; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Cell Proliferation; Contrast Media; Female; Fluorodeoxyglucose F18; Humans; Imidazoles; Indazoles; Indoles; London; Male; Middle Aged; Multimodal Imaging; Neoplasm Metastasis; Neoplasms, Second Primary; Positron-Emission Tomography; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Treatment Outcome

Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors.. In this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics.. Twenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139-427) and 494 (227-761) μg.h/mL at Day 1, and 738 (487-989) and 1071 (678-1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion.. The combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination.. The study was retrospectively registered on ClinicalTrials.gov (number NCT01202032 ) on 2010, Sept 14th.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Combined Modality Therapy; Drug Monitoring; Female; Humans; Indazoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Pyrimidines; Sulfonamides; Treatment Outcome

Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Grading; Nephrectomy; Placebos; Pyrimidines; Sulfonamides; Young Adult

The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment.. Treatment-naïve patients received pazopanib according to standard of care. Stereotactic body radiotherapy (SBRT) was delivered concurrently to the largest metastatic lesion at day 8, 10 and 12. SBRT doses were escalated in 3 dose levels (24 Gy/3, 30 Gy/3 and 36 Gy/3). Dose level was assigned using Time-to-Event Continual Reassessment Method with the target dose-limiting toxicity rate set to 0.25.. Thirteen patients were included. One patient experienced dose limiting toxicity (DLT) at dose level 3 (grade 4 hypoglycemia). Maximum tolerated dose was not reached with a recommended dose of 36 Gy/3 having a probability of DLT of 11%. One-year local control was 83% (95% confidence interval 61-100) and 1-year progression-free survival was 28% (95% confidence interval 1-55).. SBRT in combination with pazopanib is well tolerated with good local control and response rates outside the radiation field.. This trial was retrospectively registered on clinicaltrials.gov( NCT02334709 ) on January 6th, 2015.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Chemoradiotherapy; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Pyrimidines; Radiosurgery; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Sulfonamides

To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma.. To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib.. This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year.. First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm).. The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life.. A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P = .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed.. Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma.. clinicaltrials.gov Identifier: NCT01408004.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Quality of Life; Sulfonamides

The current treatment of metastatic renal cell carcinoma (mRCC) revolves around targeted agents, which have resulted in a median overall survival of 22 to 26 months in registration trials. However, the outcomes in a non-trial, real-world Indian population have not yet been evaluated.. The present study was a part of a prospective Clinical Trials Registry-India-registered study, the Kidney Cancer Registry, a prospectively maintained kidney cancer registry. The data of patients with a diagnosis of mRCC from February 2007 to August 2015 who were potential candidates for systemic therapy were extracted from the database and analyzed for treatment patterns and outcomes.. The data from 212 patients were eligible for analysis. Of these 212 patients, 204 (96.2%) received first-line systemic treatment with sunitinib (40.6%), sorafenib (37.7%), pazopanib (2.8%), temsirolimus (2.8%), or everolimus (1.9%). The risk status of 91% of the patients could be stratified using the Heng criteria into favorable (18.9%), intermediate (43.9%), and poor risk (28.3%) categories. The response rate, clinical benefit rate, median progression-free survival, and median overall survival with first-line targeted therapy were 22.5%, 60.7%, 7.09 months, and 12.87 months, respectively. The common adverse events seen included skin rash (31.7%), hypertension (29.4%), grade 3 hand-foot syndrome (27.4%), mucositis (26.4%), dyslipidemia (20%), and hyperglycemia (17.6%). Patients receiving second-line therapy (22.6%) had superior overall survival to patients who had not (16.46 vs. 10.67 months; P = .032).. The present registry-based study is the first, to the best of our knowledge, of its type from India and showed that the overall outcomes in this real-world cohort appear comparable to non-trial data worldwide. An increased incidence of metabolic adverse events that require monitoring during treatment was also found.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; India; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Practice Patterns, Physicians'; Prospective Studies; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Tertiary Care Centers; Treatment Outcome; Young Adult

Topics: Acetylation; Adult; Aged; Alanine Transaminase; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Benzofurans; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Drug Resistance; Drug Resistance, Neoplasm; Epigenesis, Genetic; Fatigue; Female; Gene Expression; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indazoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Pyrimidines; Sulfonamides; Thrombocytopenia; Treatment Outcome; Vascular Endothelial Growth Factor A; Young Adult

Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients.. Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus.. We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011-April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used.. In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% (n = 35) for pazopanib, 64% (n = 25) for bevacizumab, and 96% (n = 44) for everolimus. At peak proteinuria, 80% (n = 28), 64% (n = 16), and 80% (n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% (n = 6) and found in the bevacizumab group.. A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria.

Topics: Adult; Aged; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cohort Studies; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Prospective Studies; Proteinuria; Pyrimidines; Retrospective Studies; Sulfonamides

Hand-foot syndrome and mucositis/stomatitis are frequent adverse events (AEs) of treatment with tyrosine kinase inhibitors in cancer therapy. Quality-of-life instruments that measure the functional consequences of these AEs are needed to assess the impact of therapeutic interventions and to guide patient care. The Hand-Foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ [formerly the Supplementary Quality of Life Questionnaire]) was used in the COMPARZ trial (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma [national clinical trial no. NCT00720941]) and the PISCES study (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer [clinicaltrials.gov NCT01064310]) to assess mouth/throat and hand/foot soreness symptoms and subsequent limitations in patients receiving pazopanib or sunitinib for metastatic renal cell carcinoma. The objective of the current analysis was to validate the HAMSIQ using data from the PISCES study.. The HAMSIQ was administered in the PISCES study at baseline and every 2 weeks over two 10-week periods to patients who were receiving pazopanib or sunitinib. Data from the first 10-week period were used to assess the feasibility, validity, and responsiveness of the HAMSIQ.. In total, ≥85% of 169 patients completed the HAMSIQ (excluding the item concerning days off work). Correlations among items within the same limitation subscale generally were high (Cronbach α ≥ .80). HAMSIQ limitation scores differentiated patients according to their baseline performance status and severity of soreness. Small-to-moderate correlations were observed for the symptoms/limitation scores and for changes from baseline scores between the HAMSIQ and the Functional Assessment of Chronic Illness Therapy fatigue survey. The HAMSIQ demonstrated responsiveness to changes in clinical status and the development of hand-foot syndrome AEs over time.. The HAMSIQ is a feasible, valid, reliable, and responsive instrument for assessing the impact of hand-foot syndrome and mucositis in patients receiving tyrosine kinase inhibitors. Cancer 2016;122:287-295. © 2015 American Cancer Society.

Topics: Adult; Aged; Carcinoma, Renal Cell; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Hand-Foot Syndrome; Humans; Indazoles; Indoles; Kidney Neoplasms; Lymph Nodes; Male; Maximum Tolerated Dose; Middle Aged; Mucositis; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Pyrimidines; Pyrroles; Quality of Life; Risk Assessment; Sulfonamides; Sunitinib; Surveys and Questionnaires; Treatment Outcome

Patients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice.. Data of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear-cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib (57.2% due to progression), 47.9% had received second-line targeted therapy, and 48.9% had died.. According to IMDC prognostic model, 19.4% had favourable risk (FR), 57.2% intermediate risk (IR), and 23.4% poor risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1%, respectively (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model.. Our results validate the IMDC model for first-line pazopanib in mRCC and confirm the effectiveness and safety of this treatment.

Topics: Adult; Aged; Carcinoma, Renal Cell; Databases, Factual; Disease-Free Survival; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Prognosis; Pyrimidines; Retrospective Studies; Risk Factors; Spain; Sulfonamides

Use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) has been reported to be associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with vascular endothelial growth factor-targeted therapies. This study was a secondary pooled analysis of two Phase III randomized controlled trials (RCTs) of patients with mRCC: NCT00334282 comparing pazopanib to placebo and NCT00720941 comparing pazopanib to sunitinib. ASI users were defined as patients using an ASI at baseline. Association with overall survival (OS; primary outcome) and progression-free survival (PFS) was evaluated using Cox proportional hazards regression. The association was adjusted in multivariable analysis for baseline systolic blood pressure (SBP), use of other antihypertensive drugs and prognostic factors comprising the Heng risk criteria for mRCC. Of 1,545 patients pooled from the two RCTs, 649 (42%) were using one or more antihypertensive drugs at baseline, 385 (59%) of which were using an ASI. In the multivariable analysis of patients using pazopanib or sunitinib, no significant association was observed between baseline ASI use and OS (hazard ratio [HR] 0.97 [95% confidence interval (CI) 0.80-1.18], p = 0.80) or PFS (HR 0.88 [95% CI 0.73-1.06], p = 0.17). Exploratory subgroup analysis of NCT00720941 highlighted that the effect of baseline ASI use on OS may differ between patients treated with sunitinib and pazopanib. In conclusion, use of ASIs at baseline was not a significant independent prognostic factor for improved survival in a pooled analysis of mRCC patients treated with pazopanib or sunitinib.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Hypertension; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Prognosis; Proportional Hazards Models; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Pazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker.. Data from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed.. Analyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN.. Neither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Blood Pressure; Carcinoma, Renal Cell; Clinical Trials as Topic; Female; Humans; Hypertension; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Patient Safety; Prognosis; Pyrimidines; Pyrroles; Quality of Life; Sensitivity and Specificity; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

In a phase 3, randomized, open-label trial (Pazopanib versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma, COMPARZ; NCT00720941), pazopanib was found to be noninferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis with a quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology.. Each patient's overall survival was partitioned into 3 mutually exclusive health states: time with grade 3 or 4 toxicity (TOX), time without symptoms of disease or grade 3/4 toxicity of treatment, and time after tumor progression or relapse (REL). The time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, and utilities were applied across the range of 0 (similar to death) to 1 (perfect health).. A total of 1110 patients were enrolled (557 on pazopanib and 553 on sunitinib). The mean TOX was 31 days (95% confidence interval, 13-48 days) longer for sunitinib versus pazopanib. In the threshold utility analysis, the difference in the Q-TWiST ranged from -11 days (utility for TOX, 1; utility for REL, 0) to 43 days (utility for TOX, 0; utility for REL, 1) in favor of pazopanib across most utility combinations. Differences were significant in less than half of the utility combinations examined, and this typically occurred when the utility for TOX was lower than the utility for REL.. Patients randomized to pazopanib had a slightly longer Q-TWiST in comparison with sunitinib patients, and this was primarily due to the reduced length of TOX.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Sunitinib; Young Adult

We analyzed the dynamics of the expression of transcription factors, VEGF and its receptor VEGFR2, serine-threonine protein kinase mTOR and activity of proteasome and calpain in patients with metastatic renal cancer during therapy with tyrosine kinase inhibitor Votrient and mTOR blocker Afinitor. The expression of hypoxic nuclear factor HIF-1α in the tumor tissue decreased during therapy with the target preparations. The decrease of VEGF and its receptor VEGFR2 was observed only in patients treated with mTOR inhibitor. The increase in calpain activity in the tumor tissue was observed in both groups. These findings extend our understanding of the mechanism of action of target anticancer preparations as allow considering the studied markers as predictors in choosing optimal therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Calpain; Carcinoma, Renal Cell; Everolimus; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Kidney Neoplasms; Middle Aged; Molecular Targeted Therapy; Nephrectomy; NF-kappa B; Pyrimidines; Sulfonamides; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Proteinuria is a common adverse effect of vascular endothelial growth factor targeted agents, particularly in metastatic renal cell carcinoma (mRCC). However, risk factors for proteinuria are poorly defined.. Data on 1392 mRCC patients using pazopanib or sunitinib were pooled from two Phase-III clinical trials. Risk factors and prognostic effect of on-therapy proteinuria were evaluated by Cox proportional hazards regression.. Any-grade (1-4) and grade 3/4 proteinuria incidence were 15.0% and 3.7%, respectively. Asian ethnicity, diabetes, baseline systolic blood pressure (SBP), pre-existing grade 1 proteinuria and prior nephrectomy were significant independent predictors of either any-grade or grade 3/4 proteinuria. Proteinuria, particularly grade 3/4 (adjusted hazard ratio 0.53 (95% confidence interval 0.30-0.92)), was associated with improved overall survival.. In mRCC patients using pazopanib or sunitinib, Asian ethnicity, diabetes, SBP, pre-existing proteinuria and prior nephrectomy were independent predictors of on-therapy proteinuria, which was associated with improved survival.

Topics: Carcinoma, Renal Cell; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Proportional Hazards Models; Proteinuria; Pyrimidines; Pyrroles; Risk Factors; Sulfonamides; Sunitinib; Survival Analysis; Vascular Endothelial Growth Factor A

The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.. To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.. Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.. Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.. The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.. Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.. Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Cytoreduction Surgical Procedures; Disease-Free Survival; Female; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Nephrectomy; Proportional Hazards Models; Pyrimidines; Sulfonamides; Treatment Outcome

Several tyrosine kinase inhibitors (TKI) are used in the treatment of metastasized renal cell carcinoma (mRCC). This article presents a feasibility study for the measurement of plasma levels of sunitinib, sorafenib and pazopanib using liquid chromatography tandem mass spectrometry (LC-MS/MS).. A total of 23 patients suffering from mRCC under treatment with sunitinib (n=16), sorafenib (n=3) and pazopanib (n=4) were included. Plasma samples (100 µl) were separated by liquid chromatographic analysis and the plasma levels of the TKIs determined by tandem mass spectrometry.. The plasma levels of sunitinib, sorafenib and pazopanib were measurable and the results reproducible. During storage of the plasma samples for 1 week at 4°C no significant decrease of the initial concentration was found. The highest plasma levels detected were 99 ng/ml for sunitinib, 9.8 µg/ml for sorafenib and 63 µg/ml for pazopanib. We could show variability in plasma levels according to changes in dosage of TKIs or during treatment-free intervals.. Measurement of TKI plasma levels using LC-MS/MS is feasible. Further clinical studies have to be conducted to examine if there are any threshold levels for the incidence of adverse events or response to treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Monitoring; Feasibility Studies; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Reproducibility of Results; Sensitivity and Specificity; Sorafenib; Sulfonamides; Sunitinib

The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy.. Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test.. HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results.. Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Renal Cell; CD8-Positive T-Lymphocytes; Female; Gene Expression; Humans; Immunohistochemistry; Indazoles; Indoles; Kidney Neoplasms; Lymphocyte Count; Macrophages; Male; Middle Aged; Prognosis; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

This multicentre, single arm, phase II study was aimed to assess the efficacy and safety of pazopanib as second-line treatment after failure of sunitinib in patients with metastatic renal cell carcinoma (mRCC) and explore biomarkers for pazopanib response. Patients received pazopanib 800mgperday. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), overall survival (OS) and safety. Serum proteins (Delta-like ligand (DLL4), Notch1, hypoxia inducible factor-1α (HIF-1α), HIF-2α, vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor receptor β (PDGFRB)) levels were measured using enzyme-linked immunosorbent assay (ELISA). 86 patients with clear cell mRCC were enrolled from December 2009 to March 2012 from three centres in Southern China. Of 85 evaluable patients, the median PFS was 5.6months (95% confidence interval (CI), 4.1-6.7months) by independent review. No complete response (CR) was observed in all patients. 13 (15.3%; 95% confidence interval [CI], 11.2-23.9%) patients achieved partial responses (PR) (ORR 15.3%). Median OS was 18.1months (95% CI, 13.2-19.8months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhoea (36.5%), increased AST (51.8%), and anaemia (60%). AEs resulted in dose reduction in 24.7% of patients. Multivariable analysis showed that higher baseline levels of DLL4 and VEGFA and lower baseline level of HIF-2α were associated with shorter PFS; only lower baseline level of HIF-2α was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. In conclusion, pazopanib was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. Baseline levels of serum DLL4, VEGFA and HIF-2α may have potential utility as biomarkers of clinical efficacy in this setting (chiCTR-TRC-13004016).

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Calcium-Binding Proteins; Carcinoma, Renal Cell; China; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Intercellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Kidney Neoplasms; Logistic Models; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Pyrimidines; Pyrroles; Risk Factors; Sulfonamides; Sunitinib; Time Factors; Treatment Failure; Vascular Endothelial Growth Factor A

Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy.. Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m(2), or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery.. A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization.. Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy in a select subset of patients who would otherwise require radical nephrectomy.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Indazoles; Kidney; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Nephrectomy; Organ Size; Prospective Studies; Pyrimidines; Retrospective Studies; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden

To develop and validate a prognostic nomogram for predicting the probability of 12-month progression-free survival (PFS) for patients receiving first-line pazopanib for advanced renal cell carcinoma (RCC).. Statistical modeling was performed with data from 557 pazopanib-treated patients in the phase 3 COMPARZ trial. A multivariable Cox model was fit using known prognostic indicators. Variables included neutrophil count, serum levels of albumin and alkaline phosphatase, time from diagnosis to treatment, and bone metastases. Data from the pazopanib arm of a placebo-controlled phase 3 trial were used for validation.. The model included ten prognostic variables and was plotted as a nomogram for predicting the probability of 12-month PFS. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of PFS. The concordance index for 12-month PFS was 0.625. Significant associations (p < 0.05) were observed between PFS and bone metastases, time from diagnosis to treatment, albumin, and alkaline phosphatase. Albumin and alkaline phosphatase appeared to be influential predictors.. The nomogram predicts, with reasonable accuracy, PFS in patients with advanced RCC receiving pazopanib, based on their baseline clinical characteristics.

Topics: Adolescent; Albumins; Alkaline Phosphatase; Bone Neoplasms; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Humans; Indazoles; Kidney Neoplasms; Nomograms; Prognosis; Pyrimidines; Sulfonamides

Sunitinib is a standard agent for the treatment of metastatic renal cell carcinoma (mRCC). The objective of the study was to evaluate efficacy and safety of pazopanib in the treatment of patients whose mRCC either progressed on sunitinib or who discontinued sunitinib due to adverse effects.. Thirty-one consecutive mRCC patients who received pazopanib after sunitinib failure were included in this retrospective single center study. Pazopanib was continued until disease progression or intolerance. Treatment response was evaluated every 8-12 weeks according to the RECIST criteria. Adverse events were recorded according to the Common Terminology Criteria for Adverse Events.. Six patients (19%, 95% CI 12-26%) achieved partial response with pazopanib, 18 (58%) had stable disease, and seven (23%) progressive disease as their best response. Of the 14 patients who received pazopanib as their second-line therapy, six (43%) responded as compared with no responses among 17 patients treated in a later line (p = 0.004). The median progression-free survival time was 7.4 months after starting pazopanib (range, 0.9-15.6 months). Patients who received pazopanib as second-line treatment had median progression-free survival of 11.0 months as compared with 3.8 months among those who received pazopanib in a later line (p = 0.031). Only one (3%) patient discontinued pazopanib due to an adverse event. The most commonly recorded adverse events were anemia, thrombocytopenia, diarrhea, fatigue, and elevation of serum creatinine concentration. Six (19%) patients had one or more grade 3 or 4 adverse events recorded.. Pazopanib has clinical activity in mRCC as second-line agent after sunitinib failure suggesting lack of complete cross-resistance. Pazopanib was associated with acceptable toxicity, and may be considered as an option after sunitinib failure.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Papillary; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Salvage Therapy; Sulfonamides; Sunitinib; Survival Rate; Treatment Failure

Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind cross-over study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference.. Patients with metastatic RCC were randomly assigned to pazopanib 800 mg per day for 10 weeks, a 2-week washout, and then sunitinib 50 mg per day (4 weeks on, 2 weeks off, 4 weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL.. Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P < .001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drug's known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness.. This innovative cross-over trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Cross-Over Studies; Double-Blind Method; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Patient Preference; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Sunitinib; Surveys and Questionnaires

A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2 weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600 mg) at Day 1 (given alone) and Day 15 (the day of the 7.5 mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/F, mean value of 0.60 L/h) presented an inter-individual variability of 40 %, and an inter-occasion of 27 %. A modest but statistically significant decrease in CL/F was observed from Day 1 to Day 15 (-16.4, 95 % confidence interval of -8.5 to -27.2 %). However, trough pazopanib concentrations observed at Day 16 (24 h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600 mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Drug Interactions; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Germany; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrimidines; Sorafenib; Sulfonamides; Survival Rate; Young Adult

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Follow-Up Studies; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

Evaluation of the safety and efficacy of pazopanib, a multikinase angiogenesis inhibitor, in a single-arm, open-label, extension study (VEG107769/NCT00387764) for placebo-treated patients with advanced renal cell carcinoma (RCC) from a randomized, double-blind, placebo-controlled phase III study (VEG105192/NCT00334282).. Patients received pazopanib 800 mg/day. The primary endpoint was the safety and tolerability of pazopanib treatment. Secondary endpoints included response rate per Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS), and overall survival (OS).. Seventy-nine placebo-treated patients from VEG105192/NCT00334282 who experienced disease progression and one pazopanib-treated patient (an exemption) were enrolled. Forty-one patients (51%) were treatment-naive; 39 (49%) were cytokine-pretreated. Median exposure to pazopanib was 9.7 months. All patients had discontinued pazopanib at the time of analysis. The most common reason for discontinuation was disease progression (61%). The most common adverse events were hypertension (45%), diarrhea (45%), hair color changes (44%), anorexia (30%), and nausea (25%). The response rate was 37.5% [95% confidence interval (CI): 26.9-48.1]; median PFS was 9.2 months (95% CI: 7.3-12.0); median OS was 23.5 months (95% CI: 16.3-28.0).. Efficacy and safety profiles for pazopanib in this extension study of patients with RCC previously treated with placebo were very similar to those observed for pazopanib-treated patients in the pivotal phase III study.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anorexia; Carcinoma, Renal Cell; Diarrhea; Disease-Free Survival; Female; Hair Color; Humans; Hypertension; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Nausea; Neoplasm Staging; Pyrimidines; Randomized Controlled Trials as Topic; Severity of Illness Index; Sulfonamides; Treatment Outcome

Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach.. This study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed.. Sixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break.. Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Female; Fluorodeoxyglucose F18; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Nephrectomy; Positron-Emission Tomography; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Radiopharmaceuticals; Sulfonamides; Sunitinib; Treatment Outcome; Vascular Endothelial Growth Factor A; Withholding Treatment

This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma.. Fifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred.. Fifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%.. Pazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; Sunitinib; Treatment Outcome

The purpose of this study is to characterize tumor growth kinetics in patients with renal cell carcinoma (RCC) after treatment with pazopanib or placebo and to identify predictive patient-specific covariates.. Different tumor growth models that included patient-specific covariates were fit to tumor growth data from Phase 2 (n = 220) and Phase 3 (n = 423) clinical trials using nonlinear mixed-effects modeling. Logistic regression was used to determine whether individual model parameters or covariates were related to occurrence of new lesions.. A modified Wang model that included a quadratic growth term and a mixture model adequately described the data. Patients in Group 1 (93 %) showed treatment-dependent tumor shrinkage followed by treatment-independent regrowth. Patients in Group 2 (7 %) showed treatment-independent tumor shrinkage that did not regrow. In Group 1, pazopanib 800 mg increased the tumor shrinkage rate by 267 % compared to placebo. Baseline tumor size was dependent on baseline hemoglobin, baseline lactate dehydrogenase, study, and prior nephrectomy. Logistic regression analysis showed that prior radiotherapy, baseline tumor size, tumor shrinkage rate, tumor regrowth rate, study, and treatment (P < 0.01 for all) were all important predictors of new lesions. Patients treated with placebo were approximately twice as likely to develop new lesions than patients treated with pazopanib.. Mathematical modeling of tumor growth kinetics can quantify the effect of anticancer therapies. Pazopanib 800 mg was shown to be an effective treatment for RCC that increased the tumor shrinkage rate by 267 % compared with placebo and reduced the likelihood of developing new lesions.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Combined Modality Therapy; Double-Blind Method; Female; Humans; Indazoles; Kidney; Kidney Neoplasms; Kinetics; Logistic Models; Male; Middle Aged; Models, Biological; Pharmacogenetics; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Tumor Burden

Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.. We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent.. The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib.. In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.

Topics: Angiogenesis Inhibitors; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Carcinoma, Renal Cell; DNA, Neoplasm; Follow-Up Studies; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Indazoles; Kidney Neoplasms; Mutation; Neoplasm Staging; Polymerase Chain Reaction; Prognosis; Pyrimidines; Signal Transduction; Sulfonamides; Survival Rate; Von Hippel-Lindau Tumor Suppressor Protein

Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.. We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.. Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).. Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

Topics: Adult; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Sunitinib

An emerging literature describes the potential for long-term survival with targeted agents, but the health-related quality of life (HR-QOL) in patients who receive chronic therapy with these agents is poorly defined.. From an institutional database including 562 patients with renal cell carcinoma (RCC), patients were identified who (1) were alive 3 years beyond initiation of systemic therapy for metastatic renal cell carcinoma (mRCC) and (2) received a targeted therapy as a component of their treatment. European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 36 (QLQ-C30) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-15) questionnaires were administered by telephone survey. Data from questionnaires were compared with historical estimates derived from pivotal studies evaluating targeted agents.. A total of 38 patients met eligibility criteria for the study, and 28 patients participated in the telephone survey. Most were male patients and had clear cell histologic type (75% for both). All patients had either good- or intermediate-risk disease by Heng criteria. The mean QLQ-C30 Global QOL score in the present cohort was higher than the mean score among patients evaluated at baseline in the phase III evaluations of pazopanib (73.5 vs. 65.8; P = .07) and everolimus (73.5 vs. 61.0; P = .007). The FKSI-15 score in the present cohort was similar to the mean score among patients evaluated at baseline in the phase III evaluation of sunitinib (45.1 and 46.5, respectively; P = .41).. In this small pilot study, long-term survivors with mRCC who received targeted therapies appear to have an HR-QOL comparable to that of patients who participated in relevant phase III studies. Given the many emerging treatment options for mRCC, the HR-QOL of long-term survivors warrants greater attention.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pilot Projects; Pyrimidines; Quality of Life; Sirolimus; Sulfonamides; Surveys and Questionnaires; Survivors; Treatment Outcome

In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported.. Treatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover.. The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215-1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events.. Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Cross-Over Studies; Diarrhea; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Treatment Outcome

In a double-blind, randomised phase III trial of advanced renal cell carcinoma patients, pazopanib 800mg QD (n=290) versus placebo (n=145) significantly prolonged progression-free survival (hazard ratio (HR)=0.46, 95% confidence interval [CI] 0.34-0.62, p-value<0.0001), without important differences in health-related quality of life (HRQoL). This post-hoc analysis evaluated time to HRQoL deterioration and whether tumour response/stabilisation was associated with HRQoL improvement.. HRQoL was assessed using EORTC QLQ-C30 and EQ-5D. Effect of pazopanib on time to ⩾20% decline from baseline in summary scores was estimated for all patients and by prior treatment. Analyses were conducted for different HRQoL deterioration thresholds. HRQoL changes were stratified by benefit and compared: complete response (CR) or partial response (PR) versus progressive disease (PD); CR/PR versus stable disease (SD), and SD versus PD.. There was a trend for pazopanib patients to be less likely than placebo patients to experience ⩾20% HRQoL deterioration in EORTC-QLQ-C-30 global health status/QOL scale (HR=0.77; 95% CI 0.57-1.03, not significant). Results by prior treatment and different HRQoL deterioration thresholds were similar. Patients with CR/PR and SD experienced significantly less HRQoL deterioration than those with PD (p<0.001, p=0.0024, respectively); mean differences between patients with CR/PR and PD exceeded the pre-determined minimally important difference (MID). Differences between patients with SD and PD did not exceed pre-determined MID. Results were generally consistent across treatment and EQ-5D summary scores.. Results support the favourable benefit-risk profile of pazopanib and suggest patients experiencing tumour response/stabilisation also may have better HRQoL compared to those without this response.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Female; Health Status; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Quality of Life; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Sorafenib; Sulfonamides

Both sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib.. Two sequential prospective single arm phase II studies investigated either 12 weeks of sunitinib (n=43) or pazopanib (n=34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800 mg once daily (OD)) and sunitinib (50 mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12 weeks of therapy.. There was no significant difference in the overall number of toxic events (grade 1-4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p>0.05). Increased grade 2-4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11-2.56] p<0.03). Sunitinib was associated with an increased grade 2-4 mucositis (16% versus 0% p=0.02) and fatigue (42% versus 15% p=0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p=0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p<0.05). There was no difference in the occurrence of asymptomatic toxicity.. This indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient's choice. Further comparative data from randomised trials are awaited.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC.. Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels.. Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure.. The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

Topics: Aged; Alanine Transaminase; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Genes, MHC Class I; Genes, MHC Class II; Genetic Markers; Hemochromatosis Protein; Histocompatibility Antigens Class I; Humans; Indazoles; Kidney Neoplasms; Male; Membrane Proteins; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyrimidines; Sulfonamides

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Double-Blind Method; Germany; Humans; Indazoles; Kidney Neoplasms; Nephrectomy; Placebo Effect; Prevalence; Pyrimidines; Risk Assessment; Risk Factors; Sulfonamides; Survival Analysis; Survival Rate

Randomized controlled trials (RCTs) of multikinase inhibitors sunitinib, sorafenib, and pazopanib have reported efficacy compared with results from placebo and interferon-α (INF-α). To date, these drugs have not been compared in head-to-head trials.. To review systematically the evidence of clinical effectiveness of multikinase inhibitors in the treatment of metastatic renal cell carcinoma (mRCC) and, via an indirect meta-analysis, to determine an optimal treatment among these agents.. A systematic literature search of MEDLINE, EMBASE, CANCERLIT, and Cochrane controlled trials register databases was performed. All RCTs of multikinase inhibitors (sorafenib, sunitinib, and pazopanib) used to treat mRCC were included. The study selection, data extraction, and quality assessment were performed independently by 2 reviewers, with all disagreements being resolved by consensus. The effects of multikinase inhibitors on progression-free survival (PFS) were compared using an indirect treatment comparison method with INF-α or placebo as a comparator.. Four studies were included. Two studies examined sunitinib or sorafenib versus IFN-α, and the other 2 studies investigated sorafenib or pazopanib versus placebo. Compared with placebo, 2 interventions reported improvement for PFS (sorafenib: hazard ratio [HR] = 0.44, P = 0.01; pazopanib: HR = 0.46, P = 0.0001), whereas only sunitinib improved PFS over IFN-α (HR = 0.539, P = 0.001). An indirect comparison suggests that sunitinib is likely to demonstrate greater clinical benefit than sorafenib in terms of PFS (HR = 0.47; 95% CI, 0.316-0.713; P < 0.001), using IFN-α as the comparator. Sorafenib was not statistically different from pazopanib using placebo as the comparator in the indirect comparison (HR = 0.957; 95% CI, 0.657-1.39; P = 0.24).. Some multikinase inhibitors have a favorably reported PFS for patients with mRCC compared with results using IFN-α or placebo. Our findings suggest that sunitinib might offer some clinical benefit over sorafenib in terms of PFS. No statistical difference was found between sorafenib and pazopanib treatments. However, these conclusions are based on 2 indirect comparisons of single RCTs. More RCTs are required to confirm these findings and investigate the clinical effectiveness of multikinase inhibitors in the treatment of mRCC.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib

Inactivation of the von Hippel-Lindau gene in clear-cell renal cell carcinomas (RCC) leads to overexpression of hypoxia inducible factor, a transcription factor regulating vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) gene expression. Pazopanib, an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor, and c-KIT, was evaluated in patients with RCC.. This phase II study was designed as a randomized discontinuation study but was revised to an open-label study on the recommendation of the data monitoring committee (based on week 12 response rate [RR] of 38% in the first 60 patients). The primary end point was changed from progressive disease rate at 16 weeks postrandomization to RR. Pazopanib 800 mg was administered orally once daily. Pazopanib 800 mg was administered orally once daily.. The study enrolled 225 patients with metastatic RCC; 155 patients (69%) were treatment naïve, and 70 patients (31%) had received one prior cytokine- or bevacizumab-containing regimen. Overall RR was 35%; median duration of response was 68 weeks. Median progression-free survival (PFS) was 52 weeks. Eastern Cooperative Oncology Group performance status of 0 and time from diagnosis to treatment of more than 1 year were correlated with prolonged PFS. Pazopanib was generally well tolerated. The most common adverse events were diarrhea, fatigue, and hair depigmentation. The most common laboratory abnormalities were elevated AST and ALT.. Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of pazopanib in advanced RCC.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Sulfonamides; Treatment Outcome

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Carcinoma, Renal Cell; Double-Blind Method; Female; Humans; Indazoles; International Agencies; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Placebos; Prognosis; Pyrimidines; Sulfonamides; Survival Rate; Treatment Outcome; Young Adult

Tyrosine kinase inhibitors (TKIs) are the backbone of the systemic treatment for patients with metastatic renal cell carcinoma (mRCC). TKIs such as pazopanib and cabozantinib can interact with other drugs concomitantly administered, particularly with proton-pump inhibitors (PPIs), possibly impacting the effectiveness of the anticancer treatment and patients outcome. Few data are available about this interaction. We conducted a multicenter retrospective observational data collection of patients with mRCC treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Univariate and multivariate analyses were performed. The aim was to describe the impact of baseline concomitant PPIs on the outcome of patients to pazopanib and cabozantinib in terms of response, progression-free survival (PFS) and overall survival (OS), toxicity, and treatment compliance. The use of PPI in our study population (301 patients) significantly influenced the effectiveness of TKIs with worse PFS (16.3 vs. 9.9 months; P < 0.001) and OS (30.6 vs. 18.4 months; P = 0.013) in patients taking PPI at TKI initiation. This detrimental effect was maintained both in the pazopanib and cabozantinib groups. The use of PPI influenced the toxicity and TKI treatment compliance with a reduction of dose or schedule modifications, and treatment interruptions in the population taking PPIs. Our study demonstrates that the use of PPIs can significantly influence the outcome and compliance of patients with mRCC to TKI treatment, suggesting the importance of a more careful selection of patients who need a gastroprotective therapy, avoiding indiscriminate use of PPIs.

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Proton Pump Inhibitors; Retrospective Studies; Tyrosine Kinase Inhibitors

Treatment for advanced renal cell carcinoma (aRCC) comprises single agent or combinations of immune checkpoint inhibitors and/or anti-angiogenic agents. Pazopanib is a multitargeted anti-angiogenic tyrosine kinase inhibitor (TKI) approved as treatment for aRCC. We noted that a number of patients receiving pazopanib developed a radiological finding of small bowel lipomatosis. To evaluate the incidence of small bowel lipomatosis in patients with aRCC on treatment with pazopanib in comparison with other tyrosine kinase inhibitors.. We identified 12 out of 208 patients receiving pazopanib to have small bowel lipomatosis and compared their clinic-radiological findings with 314 patients with aRCC receiving other TKIs (sunitinib, cabozantinib, axitinib, and tivozanib). No patients receiving these TKIs developed small bowel lipomatosis.. We compared the radiological findings in patients receiving pazopanib for aRCC. The presence of lipomatosis should not be considered as a clinically relevant finding in these patients. The presence of lipomatosis has no relation with the response to treatment to pazopanib and this is a unique finding seen only in patients on pazopanib.. Small bowel lipomatosis is an occasional finding in patients with advanced renal cancer on pazopanib and is not seen with other TKIs.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Lipomatosis; Protein Kinase Inhibitors; Sunitinib

The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; East Asian People; Humans; Indazoles; Kidney Neoplasms; Sarcoma; Soft Tissue Neoplasms

Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and nivolumab have shown significant improvement in the median progression-free survival and overall survival among patients with mRCC. In this study, we aimed to determine the cost-effectiveness of the first-line treatment options for the patients with mRCC in India.. A Markov state-transition model was used to measure the lifetime costs and health outcomes associated with sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab among patients with first-line mRCC. Incremental cost per quality-adjusted life-year (QALY) gained with a given treatment option was compared against the next best alternative and assessed for cost-effectiveness using a willingness to pay threshold of one-time per capita gross-domestic product of India. The parameter uncertainty was analyzed using the probabilistic sensitivity analysis.. We estimated the total lifetime cost per patient of ₹ 0.27 million ($3,706 US dollars [USD]), ₹ 0.35 million ($4,716 USD), ₹ 9.7 million ($131,858 USD), and ₹ 6.7 million ($90,481 USD) for the sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab arms, respectively. Similarly, the mean QALYs lived per patient were 1.91, 1.86, 2.75, and 1.97, respectively. Sunitinib incurs an average cost of ₹ 143,269 ($1,939 USD) per QALY lived. Therefore, sunitinib at current reimbursement rates (₹ 10,000 per cycle) has a 94.6% probability of being cost-effective at a willingness to pay threshold of 1-time per capita gross-domestic product (₹ 168,300) in the Indian context.. Our findings support the current inclusion of sunitinib under India's publicly financed health insurance scheme.

Topics: Carcinoma, Renal Cell; Cost-Benefit Analysis; Humans; Ipilimumab; Kidney Neoplasms; Nivolumab; Sunitinib

Metastatic renal cell carcinoma (mRCC) treatment is still largely based on TKI use. Treatment adjustment due to toxicities is often needed. The aim of the present study was to determine the impact of treatment modifications on the outcome of mRCC patients treated with cabozantinib or pazopanib.. This retrospective multicenter study enrolled consecutive patients receiving cabozantinib or pazopanib between January 2012 and December 2020. We evaluated the correlation of TKI treatment modifications with grade 3-4 toxicities and progression-free (PFS) and overall survival (OS). We also performed a landmark analysis excluding patients who did not undergo at least 5 months of therapy.. Among 301 patients, 179 (59%) were treated with pazopanib, 122 (41%) with cabozantinib. Treatment modifications were related to grade 3-4 toxicities (. Tailoring treatment with pazopanib and cabozantinib was associated with better PFS/OS.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Retrospective Studies; Treatment Outcome

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Interferon-alpha; Kidney Neoplasms; Pyrroles; Sunitinib

The authors intend to compare the effects of each targeted therapy (TT) in the treatment of patients with metastatic renal cell carcinoma (mRCC) using big data based on the Korean National Health Insurance System (NHIS) and determine the optimal treatment sequence.. Data on the medical use of patients with kidney cancer were obtained from the NHIS database from January 1, 2002, to December 31, 2020. Patient variables included age, sex, income level, place of residence, prescribing department, and duration from diagnosis to the prescription date. The primary outcome was overall survival (OS) for each drug and sequencing. We performed propensity score matching (PSM) according to age, sex, and Charlson Comorbidity Index based on the primary TTs.. After 1:1 PSM, the sunitinib (SUN) (n = 1,214) and pazopanib (PAZ) (n = 1,214) groups showed a well-matched distribution across the entire cohort. In the primary treatment group, PAZ had lower OS than SUN (HR, 1.167; p = 0.0015). In the secondary treatment group, axitinib (AXI) had more favorable OS than cabozantinib (CAB) (HR, 0.735; p = 0.0118), and everolimus had more adverse outcomes than CAB (HR, 1.544; p < 0.0001). In the first to second TT sequencing, SUN-AXI had the highest OS; however, there was no statistically significant difference when compared with PAZ-AXI, which was the second highest (HR, 0.876; p = 0.3312). The 5-year survival rate was calculated in the following order: SUN-AXI (51.44%), PAZ-AXI (47.12%), SUN-CAB (43.59%), and PAZ-CAB (34.28%). When the four sequencing methods were compared, only SUN-AXI versus PAZ-CAB (p = 0.003) and PAZ-AXI versus PAZ-CAB (p = 0.017) were statistically significant.. In a population-based RWD analysis of Korean patients with mRCC, SUN-AXI sequencing was shown to be the most effective among the first to second TT sequencing methods in treatment, with a relative survival advantage over other sequencing combinations. To further support the results of this study, risk-stratified analysis is needed.

Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Republic of Korea; Sunitinib

To identify prognostic inflammatory markers in metastatic renal cell carcinoma (mRCC) patients who received anti-vascular endothelial growth factor receptor (VEGFR) agents.. Observational study. Place and Duration of the Study: Department of Medical Oncology, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey, between January 2015 and December 2021.. A total of 110 patients with mRCC who received sunitinib or pazopanib for at least 3 months were enrolled. Hemogram, C-reactive protein (CRP) and albumin values of the patients, CRP to albumin ratio (CAR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutrition index (PNI) and systemic inflammatory response indexes (SIRI) were calculated and recorded. Progression-free survival and overall survival analyses of the patients were performed using the Kaplan-Meier method. Cox regression method was used to identify prognostic factors. Variables found to be significant in univariate analysis were enrolled in multivariate analysis.. In the univariate analysis for median overall survival (mOS), whether or not surgery was applied as the primary treatment option, grade, lymphovascular invasion (LVI), International Metastatic RCC Database Consortium (IMDC) score, CAR, NLR, PLR, SII, PNI and SIRI were found to be statistically significant. Systemic inflammation markers (CAR, NLR, PLR, PNI, SII and SIRI) were found to be independent prognostic markers for mOS as a result of Cox multivariate analysis.. CAR, NLR, PLR, SII, PNI, and SIRI values measured before anti-VEGFR treatment in patients with mRCC may be of additional prognostic significance. These markers, which are calculated by using parameters that are always measured in routine practice, such as complete blood count (CBC), albumin, and CRP levels, are easy and inexpensive methods that give an idea about the course of the disease.. Sunitinib, Pazopanib, Renal cell carcinoma, Prognostic marker, Overall survival, Inflammatory.

Topics: C-Reactive Protein; Carcinoma, Renal Cell; Humans; Inflammation; Kidney Neoplasms; Neutrophils; Prognosis; Retrospective Studies; Sunitinib; Tyrosine Kinase Inhibitors

Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment due to adverse events (AEs). We established an ambulatory care pharmacy practice that enables pharmacist-urologist collaboration to manage patients with RCC. This study evaluated the usefulness of this collaborative management. We retrospectively reviewed the medical records of 51 consecutive patients with metastatic RCC receiving pazopanib at the Kobe City Medical Center General Hospital between April 2014 and December 2020. Our collaborative management was implemented in October 2016. The time to pazopanib discontinuation was compared between patients who started pazopanib before (n = 30) and after (n = 21) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with pazopanib discontinuation. In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations, and provided 286 suggestions [according to supportive care in pazopanib treatment (214 suggestions) were most frequent], and 236 (82.5%) were accepted by urologists. The median time to discontinuation (6.1 months vs. 2.4 months, p = 0.024) was significantly longer in the after group. Multivariate analysis showed that collaborative management (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.26-0.88, p = 0.017), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47-9.13, p = 0.008) were significantly associated with pazopanib discontinuation. These results suggested that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pharmacists; Retrospective Studies; Treatment Outcome; Urologists

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the metastatic renal cell carcinoma (mRCC) therapeutic landscape. Nevertheless, tyrosine-kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) axis still play a key role. The aim of the present study was to explore the prognostic performance of an integrated blood score, based on hemoglobin (Hb) concentration, mean corpuscular volume (MCV), and red cell distribution width (RDW), in mRCC patients treated with anti-VEGF TKIs. The primary endpoint was to correlate Hb, MCV, and RDW with progression-free survival (PFS) and overall survival (OS).. Our multicenter retrospective observational study involved mRCC patients treated with pazopanib or cabozantinib from January 2012 to December 2020 in nine Italian centers. Clinical records and laboratory data, including Hb levels, MCV, and RDW, were collected at baseline. Descriptive statistics and univariate and multivariate analyses were performed.. We enrolled 301 mRCC patients of which 179 (59%) underwent pazopanib, and 122 (41%) cabozantinib. We considered baseline Hb ≥12 g/dL, MCV >87 fL, and RDW ≤16% as good prognostic factors; hence, developing a multiparametric score capable of delineating 4 different categories. The number of good prognostic factors was associated with significantly longer PFS and OS (. Our analyses demonstrate the prognostic role of a multiparametric score based on easily exploitable blood parameters, such as Hb concentration, MCV, and RDW. The red blood cell-based score may underlie the upregulation of the HIF-1α pathway and VEGF axis, thereby identifying a selected population who is likely to benefit from TKI therapy.

Topics: Carcinoma, Renal Cell; Erythrocytes; Hemoglobins; Humans; Kidney Neoplasms; Prognosis; Vascular Endothelial Growth Factor A

With the rapidly evolving of immune checkpoint inhibitors (ICIs), it has shown remarkable clinical benefits in treating various cancers. However, immune-related adverse events (irAEs) remain a significant challenge in the management of patients undergoing immunotherapy. There are limited data about immunotherapy re-challenge in patients with renal clear cell cancer who had irAE in the initial ICI therapy. In this study, we reported the case of a patient with advanced renal clear cell cancer who developed serious irAEs but also achieved a partial remission of tumor after ICI combined with pazopanib in the first-line treatment. After intravenous methylprednisolone therapy for two weeks, the patient fully recovered from treatment-related toxicities. After a multidisciplinary treatment (MDT) discussion and a communication with the patient, the decision was made to undergo a new fully humanized programmed death 1 (PD-1) agent, zimberelimab, combined with pazopanib for immune restart therapy. After two cycles of treatment, the patient demonstrated a partial response (PR), and the disease remained in continuous remission without any irAE at our last follow-up after 14 months' treatment. Re-challenging with immunotherapy after irAEs is an emerging strategy that offers the potential for additional clinical benefits to previously responding patients. However, careful patient selection and monitoring are essential to maximize the safety and efficacy of this approach.

Topics: Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Indazoles; Kidney Neoplasms

Recently, combination therapy including immune checkpoint inhibition (ICI) has proven to be effective as first-line therapy for patients with metastatic renal cell carcinoma. Although the first-line combination therapies with ICI have shown clinical benefit, a number of patients require second-line treatment. We report a 60-year-old man with metastatic renal cell carcinoma who was treated with pazopanib soon after nivolumab plus ipilimumab combination therapy. He experienced Grade 3 disseminated intravascular coagulation (DIC). We suspect that this was caused by an interaction between pazopanib and nivolumab even though ICI therapy was discontinued. He was treated with thrombomodulin and platelet transfusion and recovered from DIC. Treatment with pazopanib was subsequently restarted. No evidence of DIC was observed thereafter. This severe adverse reaction may have been induced by an interaction between activated proinflammatory immune cells and cytokines from an exacerbated inflammatory state and pazopanib. This report highlights the need to perform careful monitoring of patients who receive molecular targeted therapy after ICI-based immunotherapy.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disseminated Intravascular Coagulation; Humans; Immune Checkpoint Inhibitors; Indazoles; Ipilimumab; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nivolumab; Pyrimidines; Sulfonamides

Pazopanib and sunitinib are oral tyrosine kinase inhibitors (TKI) approved for the treatment of renal cell carcinoma. For both oncolytics, a clear target trough concentration level in plasma has been defined above which improved clinical efficacy can be expected. However, many factors can alter TKI exposure, including disease characteristics.. A 79-year old male with metastatic papillary renal cell carcinoma and malignant ascites was treated with pazopanib. Initially, treatment with pazopanib at adequate trough concentrations resulted in regression of ascites. After a 6-month puncture-free interval, paracenteses were again required and the plasma trough concentration of pazopanib had decreased to 5 mg/L without any dose adjustments. Despite a dose increase, pazopanib levels remained subtherapeutic and could not prevent new paracenteses. Pazopanib concentrations in the drained ascites fluid were comparable to plasma concentrations and remained high also after treatment discontinuation. This observation suggests that the ascites compartment may act as a third space in which pazopanib accumulates. During subsequent treatment with sunitinib, a similar distribution over ascites fluid was observed.. Presence of ascites or pleural effusion in patients treated with TKIs may lead to subtherapeutic plasma exposure, which may hamper treatment efficacy. Measuring TKIs plasma concentrations regularly during treatment is essential to identify patients with subtherapeutic exposure.

Topics: Aged; Ascites; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Humans; Indazoles; Kidney Neoplasms; Male; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Sunitinib; Treatment Outcome

Sunitinib and pazopanib are tyrosine kinase inhibitors (TKIs) used as first-line therapy for metastatic renal cell carcinoma (RCC). Although these TKIs are associated with similar survival outcomes, some differences have been reported in their safety profiles. In this work, traditional toxicological endpoints (cell viability and growth, oxidative stress, and nuclear morphology) and

Topics: Amino Acids; Antineoplastic Agents; Carcinoma, Renal Cell; Glycerophospholipids; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip

Topics: Anilides; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Nerve Growth Factors; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinolines; src-Family Kinases; Sulfonamides; Sunitinib

Pazopanib is an oral multi-kinase inhibitor approved for the treatment of advanced renal cell carcinoma (RCC). It is an anti-angiogenic agent, which blocks the activation signaling pathways of tyrosine kinases and prevents the activities of primarily vascular endothelial growth factor receptors (VEGFR)-2 and VEGFR-3, which are important in lymphangiogenesis. Herein, we report a patient with advanced RCC who developed asymptomatic left-sided chylothorax under pazopanib therapy. Chylothorax developed in the 16th month and gradually increased until it was diagnosed by thoracentesis in the 22nd month. The development of chylothorax was attributed to pazopanib therapy after ruling out all possible traumatic and nontraumatic etiologies. The 'Adverse Drug Reaction Probability Scale' revealed a total score of 6, which fell into 'probable' category. Chylothorax regressed significantly 5 weeks after the discontinuation of pazopanib therapy.

Topics: Adult; Antineoplastic Agents; Carcinoma, Renal Cell; Chylothorax; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States. Painkillers and fever antipyretics are the most common cause of DILI. Hepatic injury can be provoked by DILI as hepatocellular or cholestatic type.. A 48-year-old woman presented jaundice accompanied by nausea and vomiting. The patient was an inactive hepatitis B carrier with low viral titer and was diagnosed renal cell carcinoma (RCC) with hepatic metastasis requiring pazopanib treatment. Prior to administration of pazopanib, tenofovir administration was started to prevent exacerbation of hepatitis B. The patient was referred to clinic of gastroenterology department due to sudden elevation of bilirubin after 5 weeks of pazopanib treatment.. Abdominal ultrasound and computed tomography showed non-specific finding other than metastatic nodule in the liver and liver cirrhosis. After then, the patient was performed liver biopsy, and the biopsy result was acute cholestatic hepatitis with centrilobular area necrosis and portal inflammation. Therefore, considering the clinical history and biopsy results, the patient was diagnosed as DILI due to pazopanib.. After the biopsy, empirical steroid therapy was initiated and after 7 weeks of pazopanib discontinuation.. The total bilirubin level returned to normal from peak level of 24.61 to 1.52 mg/dL.. In patients with renal cell carcinoma, pazopanib treatment requires clinical caution as it causes rare complications such as severe jaundice and acute cholestatic hepatitis.

Topics: Bilirubin; Biopsy; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Female; Hepatitis B; Humans; Indazoles; Jaundice; Kidney Neoplasms; Middle Aged; Nausea; Pyrimidines; Steroids; Sulfonamides; Tomography, X-Ray Computed; Ultrasonography; United States; Vomiting

There is poor data on the prognostic role of Comprehensive Geriatric Assessment (CGA) in older patients with metastatic renal cell carcinoma (mRCC) treated with first line Tyrosine Kinase Inhibitors (TKIs).. We retrospectively reviewed the clinical charts of mRCC patients older than 70 years treated at our Institute with first-line Sunitinib or Pazopanib for at least 6 months. Every patient received a CGA at baseline and was identified as fit, vulnerable or frail according to Balducci's Criteria. We then assessed the impact of CGA category on survival, disease control and tolerability of TKIs.. We identified 86 eligible patients. Median age: 74.5 years, 56% males; 45.4% were fit, 37.2% vulnerable and 17.4% frail at CGA. There were no significant differences in the rate of Grade (G)1-2 and G3-4 toxicities, dose reduction rates, PFS and OS between Sunitinib and Pazopanib. Fit, vulnerable and frail patients achieved significantly different median PFS (18.9 vs 11.2 vs 5.1 months; p < 0.001) and OS (35.5 vs 14.6 vs 10.9 months; p < 0.001). Patients categorized as fit had higher chance of receiving a second-line treatment (66.6% vs 28.9% in vulnerable/frail; p = 0.002). The incidence of G3/4 events was significantly lower in the fit subgroup (19% vs 45% in vulnerable/frail; p = 0.0025).. In our retrospective single-center experience, CGA could accurately discriminate patients with higher risk of experiencing G3/4 toxicities, shorter PFS, and lower chance of receiving a second line treatment. CGA strongly impacted on OS, independently from International mRCC Database Consortium (IMDC) classification.

Topics: Aged; Carcinoma, Renal Cell; Disease-Free Survival; Female; Geriatric Assessment; Humans; Indazoles; Kidney Neoplasms; Male; Prognosis; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome

Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials.. Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan-Meier curves, log-rank test and multivariable Cox's models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose.. Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium's good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium's favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged.. In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium's favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium's good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.

Topics: Adult; Aged; Carcinoma, Renal Cell; Databases, Factual; Female; Humans; Indazoles; Italy; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Proportional Hazards Models; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome

A 71-year-old female was diagnosed with localized renal cell carcinoma in July 2008 with subsequent metastasis in 2012 to the right adrenal gland, lungs, and brain. Due to disease progression, she was started on pazopanib 800 mg daily in October 2012. In November 2016, the patient developed an ill-defined, red, 10 × 15 cm indurated plaque on the left lateral upper thigh with a discrete 3 cm firm tender tumor without ulceration. An incisional biopsy was performed and showed panniculitis with features resembling sclerosing lipogranuloma. Alternative causes including rheumatologic disease and trauma were ruled out. We report the first case of pazopanib-induced panniculitis. Key clinical and histopathological features include tender subcutaneous nodules, exclusion of other causes, and fatty microcysts within a densely sclerotic background on pathology. As targeted therapies are becoming increasingly common in the field of oncology, prompt identification and reporting of adverse reactions is critical for proper management.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Panniculitis; Pyrimidines; Sulfonamides

Predictive markers can help tailor treatment to the individual in metastatic renal cell carcinoma (mRCC). De Ritis ratio (DRR) is associated with oncologic outcomes in various solid tumors.. To assess the value of DRR in prognosticating survival in mRCC patients treated with tyrosine-kinase inhibitors (TKI).. Overall, 220 mRCC patients treated with TKI first-line therapy were analyzed. An optimal cut-off point for DRR was determined with Youden's J. We used multiple strata for DRR, performed descriptive, Kaplan-Meier and multivariable Cox-regression analyses to assess associations of DRR with progression-free (PFS) and overall survival (OS).. Patients above the optimal cut-off point for DRR of ≥ 1.58 had fewer liver metastases (p = 0.01). There was no difference in PFS (p > 0.05) between DRR groups. DRR above the median of 1.08 (HR 1.42; p = 0.03), DRR ≥ 1.1(HR 1.44; p = 0.02), ≥ 1.8 (HR 1.56; p = 0.03), ≥ 1.9 (HR 1.59; p = 0.02) and ≥ 2.0 (HR 1.63; p = 0.047) were associated with worse OS. These associations did not remain after multivariable adjustment. In the intermediate MSKCC group, DRR was associated with inferior OS at cut-offs ≥ 1.0 (HR 1.78; p = 0.02), ≥ 1.1 (HR 1.81; p = 0.01) and above median (HR 1.88; p = 0.007) in multivariable analyses. In patients with clear-cell histology, DRR above median (HR 1.54; p = 0.029) and DRR ≥ 1.1 (HR 1.53; p = 0.029) were associated with OS in multivariable analyses.. There was no independent association between DRR and survival of mRCC patients treated with TKI in the entire cohort. However, OS of patients with intermediate risk and clear-cell histology were affected by DRR. DRR could be used for tailored decision-making in these subgroups.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Carcinoma, Renal Cell; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Karnofsky Performance Status; Kidney Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Nephrectomy; Predictive Value of Tests; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis

Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches.. We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1.. We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event.. To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anilides; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Humans; Immune Checkpoint Inhibitors; Indazoles; Ipilimumab; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinolines; Retrospective Studies; Sulfonamides; Survival Rate; Treatment Outcome

Translocation renal cell carcinoma (TRCC) is a rare form of RCC affecting mostly children and young adults with the occurrence of only 1-5% of all renal cell carcinomas. These carcinomas are associated with different translocations on a short arm of chromosome X in the region 11.2, which results in genetic modification of the p arm containing the transcription factor E3 gene.. Herein we report a case of a patient who was dia-gnosed with TRCC with c-Met overexpression and was treated with multiple targeted therapy agents and immunotherapy.. A 28-year old woman without a significant past medical history underwent left sided total nephrectomy for TRCC. Seven months later, she developed systemic relapse and was treated with multiple lines of targeted therapy including sunitinib, everolimus, sorafenib, crizotinib, and pazopanib as well as with anti-PD-L1 antibody nivolumab, with stable disease as a best response. The most pronounced disease stabilization was achieved with sorafenib, which lasted 18 months. The patient died 81 months after initial dia-gnosis and 74 months from the dia-gnosis of metastatic disease.. Improved survival observed in our patient could be related to the effectivity of tyrosine-kinase inhibitors, but notm-TOR inhibitors, even though disease stabilisation was observed as a best response. Identification of new treatment targets are warranted in this rare disease.

Topics: Adult; Antineoplastic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carcinoma, Renal Cell; Chromosomes, Human, X; Crizotinib; Disease Progression; Everolimus; Fatal Outcome; Female; Humans; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Nivolumab; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrimidines; Sorafenib; Sulfonamides; Sunitinib; Tomography, X-Ray Computed

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Nephrectomy; Pyrimidines; Sulfonamides; Survival Analysis

Xp11.2 translocation renal cell carcinoma (TRCC) is a rare and aggressive variant of renal cell carcinoma (RCC) when presenting in adults. We report a case of a man in his early 40s who was diagnosed with stage III Xp11.2 TRCC and underwent radical nephrectomy. Seven months following the surgery, an adrenal nodule and bilateral pulmonary nodules were discovered. He underwent cryoablation of the adrenal nodule and systemic treatment with daily pazopanib. He displayed stable disease for approximately 6 years. Following this period, multiple hospitalisations interrupted daily pazopanib therapy resulting in progression of disease. His regimen was then changed to ipilimumab and nivolumab, followed by current daily therapy with axitinib. The patient now shows stable disease in his 10th year after diagnosis. This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation to supplement the guidelines regarding the use of targeted therapy for TRCC.

Topics: Adult; Carcinoma, Renal Cell; Chromosomes, Human, X; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides; Translocation, Genetic

The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms.. We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14. Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells.. The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.

Topics: Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Immunomodulation; Indazoles; Kidney Neoplasms; Male; Myeloid-Derived Suppressor Cells; Prognosis; Pyrimidines; Sulfonamides; Survival Rate; Transcriptome; Tumor Cells, Cultured; Tumor Microenvironment

Renal cell carcinoma (RCC) is one of the most common solid tumors in adults highly resistant to conventional therapies. The expression profile of a number of miRNAs correlates with RCC response to chemotherapeutic agents.. To identify the association of tumor miRNAs expression with neoadjuvant treatment response in patients with RCC.. We analyzed the expression levels of tumor miR-99b, -144, -155, -210, -222, -302а, -377 in 93 RCC patients who received pazopanib or sunitinib in neoadjuvant regimen using RT-PCR. RNU48 was used as a reference miRNA.. The levels of expression of miR-99b and -377 are associated with the RCC response to pazopanib, and microRNA-210 and -377 to sunitinib. The characteristic expression profile of miR-99b, -144, -222, -377, and miR-302a determined in 90% of cases was delineated in pazopanib responders as opposed to nonresponders. Similarly, the characteristic expression profile of miR-210, -222, -302a and -377 was suggested for sunitinib responders.. Levels of miR-99b, -210 and -377 expression in RCC tumor tissue might be used as a basis for future predictive panel intended for the assessment of the sensitivity to the regimens of neoadjuvant RCC treatment.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Kidney Neoplasms; Male; MicroRNAs; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome

Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear.. Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC.. The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors.. The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p < 0.001) and OS (HR 0.641, p = 0.006). The median PFS and OS for users of BBs was 18.39 and 37.60 months versus 8.16 and 20.4 months for patients not using BBs (p < 0.001 and p < 0.001, respectively). The Cox multivariate analysis showed that the use of BBs was a significant factor for both PFS (HR 0.428, p = 0.001) and OS (HR 0.518, p = 0.001).. The results of this retrospective study suggest that the use of BBs is associated with favorable outcomes for patients with mRCC treated with sunitinib or pazopanib in the first line.

Topics: Aged; Carcinoma, Renal Cell; Cardiovascular Agents; Disease-Free Survival; Humans; Indazoles; Indoles; Kidney Neoplasms; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome

Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes.. Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods.. Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P = .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P = .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism.. UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glucuronosyltransferase; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Liver Function Tests; Longitudinal Studies; Male; Middle Aged; Polymorphism, Genetic; Progression-Free Survival; Prospective Studies; Pyrimidines; Retrospective Studies; Sulfonamides

In the first-line (1L) setting, pazopanib (PAZ) has been recommended by the National Comprehensive Cancer Network for the treatment of advanced renal cell carcinoma (aRCC). In 2018, immuno-oncology (IO) therapy became a commonly used 1L treatment option for aRCC. We report the real-world clinical outcomes of PAZ after IO therapy for patients with aRCC.. We performed a longitudinal, retrospective medical record review study. The included patients were aged ≥ 18 years, had initiated second-line and/or beyond PAZ after IO therapy for clear cell aRCC on or before October 2017, and had complete medical records available from the diagnosis of aRCC to the discontinuation of PAZ, death, or the medical record extraction date (May 2018), whichever occurred first. The primary outcome variable was the PAZ duration of therapy. The secondary outcomes were progression-free survival and overall survival since PAZ initiation, the reasons for PAZ discontinuation, and the occurrence of adverse events (AEs).. A total of 258 eligible patients had initiated IO therapies before PAZ as follows: nivolumab (68%), nivolumab plus ipilimumab (14%), pembrolizumab (12%), and ipilimumab (3%). Overall, the median PAZ duration of therapy was 13.4 months (95% confidence interval [CI], 10.1-16.0 months). The median progression-free survival with PAZ after IO therapy was 13.5 months (95% CI, 11.8 months to not reached). The estimated overall survival rate of PAZ after IO therapy at 6 and 12 months was 93% and 89%, respectively. A total of 109 patients (42%) had reported an AE. The most frequently reported AEs were fatigue (29%) and diarrhea (14%). No additional safety signal of hepatotoxicity was observed (increased aspartate aminotransferase, 5%; increased alanine transaminase, 6%).. In the present real-world study, second-line and/or beyond PAZ after previous IO therapy was well-tolerated and effective for patients with aRCC.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Diarrhea; Fatigue; Female; Humans; Indazoles; Ipilimumab; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Time Factors

Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib.. A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient's therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made.. Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Carcinoma, Renal Cell; Drug Therapy, Combination; Edema; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Sulfonamides; Synovitis

Anti-angiogenic tyrosine kinase inhibitors, sunitinib and pazopanib, have proven efficacy in advanced renal cell carcinoma, with specific adverse events occurring during treatment process. Comorbidities can reflect functional status and have prognostic value in oncology patients. We aimed to assess the association of the Charlson Comorbidity Index with severe toxicities and mortality in renal cell carcinoma cases treated with front-line sunitinib or pazopanib.. Files of locally advanced and metastatic renal cell carcinoma patients who received first-line sunitinib or pazopanib were retrospectively examined. Charlson Comorbidity Index of each patient was calculated. Patients were also stratified into Memorial Sloan-Kettering Cancer Center risk groups. Predictors of dose-limiting toxicity were evaluated with binomial logistic regression analysis. Univariate and multivariate Cox regression models were utilized to determine prognostic factors for survival.. The study included 102 patients, 64 were treated with first-line sunitinib and 38 with pazopanib. In 42 patients (41.9%), Charlson Comorbidity Index was 9 or more. Dose-limiting toxicities were significantly more frequent in Charlson Comorbidity Index ≥9 group (69% vs. 40%, p = 0.004), and Charlson Comorbidity Index independently predicted dose-limiting toxicity (Hazard ratio (HR) = 4.30, p = 0.002). After adjusting for other variables, a Charlson Comorbidity Index of ≥9 is also a significant prognostic factor for progression-free (HR = 1.76, p = 0.02) and overall survival (HR = 1.75, p = 0.03).. Charlson Comorbidity Index may be a valuable method to estimate prognosis and optimize therapy in patients with advanced renal cell carcinoma receiving first-line sunitinib or pazopanib.

Topics: Aged; Aged, 80 and over; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib

To identify the optimum response criteria for first-line targeted pazopanib therapy in patients with mRCC using solid tumor response criteria and clinical risk factors.. Pre- and post-treatment CTs of patients (n = 43) with mRCC treated with first-line pazopanib therapy were analyzed retrospectively. Treatment response was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Choi, modified Choi (mChoi), revised Choi (rChoi), MASS (Morphology, Attenuation, Size, and Structure), 10% threshold criteria, and subjective assessment. Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium clinical risk factors were also used to define response groups. Response evaluations were correlated with overall survival (OS) and progression-free survival (PFS) using log-rank test.. Patients with partial response (PR) by mChoi and rChoi had longer OS than those with stable disease (SD) (P < 0.001). Responders by 10% threshold criteria also had better OS, without or combined with clinical criteria. Patients with PR by rChoi, mChoi, RECIST v1.1, MASS criteria, and by subjective assessment had longer PFS than those with SD. rChoi and mChoi criteria best delineated the difference in PFS for patients with PR versus SD, without or combined with clinical criteria.. For mRCC patients treated with pazopanib, OS and PFS for PR and SD groups were best predicted by rChoi and mChoi criteria, without or combined with clinical risk factors. 10% threshold criteria also predicted OS and PFS, whereas RECIST did so only in a limited number of patients.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome

The objective of this study was to determine the outcomes of young adults with kidney cancer treated during the targeted therapy era and evaluate the impact of young age on survival.. We reviewed the records from 445 patients younger than 55 years with kidney cancer at a single institution from 2006 to 2017. Overall survival (OS) and recurrence-free survival were estimated with the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to determine the impact of clinical and pathologic variables on all-cause mortality.. Overall, 104 (23%) patients 40 years or younger were compared with 341 (77%) patients who were 41 to 55 years old. Younger patients presented with more advanced stages of the disease, including metastasis at diagnosis, positive lymph nodes, venous tumor thrombus and had more non-clear cell tumors (54% vs. 30%; P < .001). Young adults had significantly worse OS at 2 and 5 years (67% vs. 82% and 53% vs. 69%, respectively). Younger patients with metastatic disease received targeted agents less often compared with the older group (64% vs. 75%). There was no difference in recurrence-free survival across patients with localized disease. Independent prognostic factors associated with increased mortality were metastasis at diagnosis, pT2 or greater, and age younger than 40 years (hazard ratio, 1.65; 95% confidence interval, 1.0-2.6; P = .03).. Patients younger than 40 years with kidney tumors treated during the targeted therapy era have worse OS compared with older adults. Young age is an independent predictor of mortality.

Topics: Adolescent; Adult; Age Factors; Carcinoma, Renal Cell; Disease-Free Survival; Female; Follow-Up Studies; Humans; Indazoles; Kaplan-Meier Estimate; Kidney; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sulfonamides; Sunitinib; Young Adult

The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.

Topics: Animals; Antineoplastic Agents; Autocrine Communication; Carcinoma, Renal Cell; Cell Line, Tumor; Chemokine CCL24; Disease Progression; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Indazoles; Kidney Neoplasms; Male; Mice, Inbred NOD; Mice, SCID; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins; Pyrimidines; Receptors, CCR3; Signal Transduction; STAT3 Transcription Factor; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Asian People; Carcinoma, Renal Cell; Drug Monitoring; Female; Humans; Indazoles; Japan; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult

We report a case of rapid evolution of polycystic liver disease in a 76-year-old patient with metastatic renal cell carcinoma who underwent treatment with numerous antineoplastic agents. The aim was to identify a causative etiology for these hepatic cysts of unclear origin. The cystic lesions of the patient were ultimately innumerable and developed rapidly, more than tripling the total liver volume from complete absence over the course of 24 months. The hepatic lesions continued to grow despite an otherwise moderate tumor response. Prior to patient death, the patient remained relatively asymptomatic from the cyst burden and was without signs of grossly metastatic disease. This rapid development of polycystic liver disease most likely represents a previously unseen medication side-effect of cabozantinib or pazopanib. It is important to identify adverse effects of novel antineoplastic agents in this time of oncological medical discovery.

Topics: Aged; Anilides; Carcinoma, Renal Cell; Cysts; Humans; Indazoles; Kidney Neoplasms; Liver Diseases; Male; Neoplasm Metastasis; Pyridines; Pyrimidines; Sulfonamides

Pazopanib is a tyrosine kinase inhibitor with hyperglycaemia as a known adverse event, but case reports of severe hyperglycaemia are exceptional. We report a case of severe hyperglycaemia following pazopanib administration in a patient with metastatic renal cell carcinoma.. Severe hyperglycaemia developed in a patient one month following initiation of pazopanib therapy. As drug-drug-gene interactions may lead to hyperglycaemia, pharmacogenetic assessment was requested. The obtained findings indicated intermediate function of both OATP1B1 and P-glycoprotein transporters, which may cause prolonged pazopanib bioavailability and increased toxicity. Pazopanib was discontinued and, following patient recovery, was reintroduced at a lower dose.. The pharmacogenetic profiling of the patient on polypharmacy enabled better management of pazopanib therapy.

Topics: Aged; Carcinoma, Renal Cell; Drug Interactions; Humans; Hyperglycemia; Indazoles; Kidney Neoplasms; Male; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time- international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.

Topics: Administration, Oral; Aged; Carcinoma, Renal Cell; Drug Interactions; Drug Monitoring; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides; Warfarin

Papillary renal cell carcinoma (papRCC) is a rare (10%-15%) subtype of renal cancer. Few prognostic biomarkers have been described in metastatic papRCC (m-papRCC) patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). We aimed to study the prognostic impact of bone metastases (BM) on response rate, progression-free and overall survival (PFS and OS) in patients with m-papRCC treated with first agent VEGFR-TKIs.. A multicentric, retrospective analysis of patient records was conducted. BM were detected by computed tomography and/or bone scintigraphy. The International Metastatic RCC Database Consortium (IMDC) score was calculated at start of first agent VEGFR-TKI treatment.. Forty-nine patients were included. Best objective response was partial response in 20%, stable disease in 60% and early progressive disease in 20% of patients. Median PFS (mPFS) was 6.0 months and median OS (mOS) 14.0 months after start of first agent VEGFR-TKI. The IMDC score correlated with mOS: 77.5 months in good, 17.0 months in intermediate and 8.0 months in poor risk patients (P = 0.002). Patients with BM had a poorer outcome compared to patients without BM: mPFS was 4.0 vs. 7.0 months (P = 0.006) and mOS 7.5 vs. 19.0 months (P = 0.002). On bivariate analysis, the presence of BM was independently associated with PFS (P = 0.02) and OS (P = 0.049), independent of the IMDC risk groups.. In m-papRCC patients treated with first agent VEGFR-TKIs, the presence of BM is an unfavorable prognostic factor, associated with shorter PFS and OS.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Axitinib; Bone Neoplasms; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; Treatment Outcome

The aim of this study was to investigate the impact of acid suppressive therapy on clinical efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma (mRCC).. A single-center retrospective study was carried out. Charts of mRCC patients who received pazopanib as first-line treatment were reviewed and concomitant use of proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was studied. Two groups of patients were identified, namely patients receiving PPI/H2RA and patients without acid suppressive therapy. Both groups were compared with regard to progression free survival (PFS), overall survival (OS), tumor response, and time to dose reduction of pazopanib.. Ninety-one patients were included. Median PFS was 8 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (hazard ratio (HR) 0.76 (95% confidence interval (CI) 0.42-1.35)), p = 0.35. Median OS was 27 months in the PPI/H2RA group vs. 23 months in the no PPI/H2RA group (HR 0.87 (95% CI 0.46-1.66)), p = 0.68. Mean tumor response was 17% (95% CI 8-25%) in the PPI/H2RA group vs. 11% (95% CI 0-21%) in the no PPI/H2RA group, p = 0.52. Median time to first dose reduction was 9 months in both subgroups (HR 1.25 (95% CI 0.65-2.39)), p = 0.51. Median time to second dose (< 600 mg) reduction was 17 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (HR 0.26 (95% CI 0.07-0.89)), p = 0.03.. In this limited patient series, no evidence of a negative impact of PPI/H2RA on clinical outcome and time to first dose reduction was observed. These results suggest that PPI/H2RA might be considered, when there is a clinical need, in patients treated with pazopanib for mRCC. However, a prospective study is warranted to confirm these results.

Topics: Aged; Carcinoma, Renal Cell; Cohort Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Histamine H2 Antagonists; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Proton Pump Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Rate; Time Factors; Treatment Outcome

Real-world evidence from clinical practices is fundamental for understanding the efficacy and tolerability of medicinal products. Patients with renal cell cancer were studied to gain data not represented by analyses conducted on highly selected patients participating in clinical trials. Our goal was to retrospectively collect data from patients with advanced renal tumours treated with pazopanib (PZ) to investigate the efficacy, frequency of side effects, and searching for predictive markers. Eighty-one patients who had received PZ therapy as first-line treatment were retrospectively evaluated. Overall survival (OS), progression-free survival (PFS) were assessed as endpoints. Median PFS and OS were 11.8 months (95% CI: 8.8-22.4); and 30.2 months (95% CI: 20.3-41.7) respectively. Severe side effects were only encountered in 11 (14%) patients. The presence of liver metastasis shortened the median PFS (5.5 vs. 14.8 months, p = 0.003). Median PFS for patients with or without side effects was 25.6 vs. 7.3 months, respectively (p = 0.0001). Patients younger than 65 years had a median OS of 41.7 months vs. 25.2 months for those over 65 years of age (p = 0.008). According to our results absence of liver metastases, younger age (<65 years) and presence of side effects proved to be independent predictive markers of better PFS and OS.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome

Metastatic renal cell carcinoma (mRCC) encompasses a heterogeneous group of neoplasms with distinct clinical behavior and prognoses. As a result of the increasing number of therapeutic options in the metastatic setting, it is crucial to improve prognostic stratification ability. We aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and combination platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with mRCC. We evaluated a cohort of mRCC patients treated with first-line pazopanib or sunitinib. Levels of NLR, PLR and COP-NLR were measured prior to systemic treatment and evaluated as prognostic predictors. Primary endpoint was overall survival (OS). Data from 276 patients were included, of which 54.7% received first-line pazopanib and 45.3%, sunitinib. Memorial Sloan-Kettering Cancer Center risk classification was intermediate and poor in 50% and 42.6% of patients, respectively. High NLR (> 3.5) was associated with inferior OS (median 9.6 vs 17.8 months, P < 0.001). A high PLR (> 200) was associated with inferior OS (median 10.3 vs 17 months, P = 0.002). The median OS in the COP-NLR 1, 2 and 3 groups were 19.0 months (95% CI 15.3-26.0), 13.1 months (95% CI 9.8-17.0) and 7.4 months (95% CI 3.6-11.9), respectively (P < 0.001). In the multivariate analysis, high NLR and high COP-NLR were associated with inferior OS. Both high NLR and high COP-NLR were associated with poorer OS in our cohort of patients with mRCC treated with first-line pazopanib or sunitinib.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Child; Female; Humans; Indazoles; Inflammation; Kidney Neoplasms; Lymphocyte Count; Male; Middle Aged; Neutrophils; Platelet Count; Prognosis; Pyrimidines; Sulfonamides; Sunitinib; Young Adult

Chromosomal rearrangements are common in clear cell renal cell carcinoma (ccRCC) and their roles in mediating sensitivity to tyrosine kinase inhibitors (TKIs) and mTOR inhibitors (mTORi) remain elusive.. We developed an in silico strategy by screening copy number variance (CNV) that was potentially related to TKI or mTORi sensitivity in ccRCC by reproducing the TCGA and GDSC datasets. Candidate genes should be both significantly prognostic and related to drug sensitivity or resistance, and were then validated in vitro.. ADCYAP1 loss and GNAS gain were associated with sensitivity and resistance and to Cabozantinib, respectively. ACRBP gain and CTBP1 loss were associated with sensitivity and resistance and to Pazopanib, respectively. CDKN2A loss and SULT1A3 gain were associated with sensitivity and resistance and to Temsirolimus, respectively. CCNE1 gain was associated with resistance to Axitinib and LRP10 loss was associated with resistance to Sunitinib. Mutivariate analysis showed ADCYAP1, GNAS, and CCNE1 remained independently prognostic when adjusted for the rest.. Here we show CNVs of several genes that are associated with sensitivity and resistance to commonly used TKIs and mTORi in ccRCC. Further validation and functional analyses are therefore needed.

Topics: Anilides; Antineoplastic Agents; Arylsulfotransferase; Axitinib; Carcinoma, Renal Cell; Carrier Proteins; Cell Line, Tumor; Chromogranins; Computer Simulation; Cyclin E; DNA Copy Number Variations; Drug Resistance, Neoplasm; GTP-Binding Protein alpha Subunits, Gs; Humans; Indazoles; Kidney Neoplasms; Oncogene Proteins; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Pazopanib is a multi-targeted tyrosine kinase inhibitor, which is indicated for use in patients with advanced renal cell carcinoma or advanced soft-tissue sarcomas. Although rare, interstitial lung disease has been reported as among the adverse sequelae of pazopanib therapy. We report the case of a 75-year-old man who developed interstitial lung disease during treatment with pazopanib for renal cell carcinoma with multiple lung metastases. The patient presented with dry cough and new-onset fatigue 3 months after initiation of pazopanib. He had mild hypoxia with bilateral ground-glass opacities on chest CT. He was treated with antibiotics for presumptive pneumonia, but his respiratory status rapidly deteriorated, and he required non-invasive positive pressure ventilation. He recovered on discontinuation of pazopanib and systemic steroids. Clinicians should recognise that interstitial lung disease can occur in patients who are undergoing treatment with pazopanib.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Pyrimidines; Sulfonamides

Patients with metastatic renal cell carcinoma (mRCC) treated with targeted systemic therapies have demonstrated favourable outcomes in randomised controlled trials, however real-world evidence is limited. Thus, this study aimed to determine the effectiveness of targeted systemic therapies for patients with mRCC in routine clinical practice in the UK.. A retrospective, observational, longitudinal study based on chart review of newly diagnosed adult mRCC patients treated at two UK hospitals from 2008 to 2015 was conducted. Targeted systemic therapies recommended for use in mRCC patients were evaluated across first to third lines of therapy (1LOT-3LOT). Important exclusions were treatment with cytokine therapy and within non-standard of care clinical trials. Primary outcome measure was overall survival (OS); data were analysed descriptively and using Kaplan-Meyer analysis.. 652 patients (65.3% male, 35.0% ≥70 years) were included. In 1LOT, 98.5% of patients received sunitinib or pazopanib. In 2LOT and 3LOT, 99.0 and 94.4% received axitinib or everolimus. Median OS was 12.9, 6.5 and 5.9 months at 1LOT, 2LOT and 3LOT respectively. Estimated OS at 1-year was 52.4% (95% CI: 48.6-56.4%) in 1LOT, 31.5% (25.2-39.5%) in 2LOT and 23.8% (10.1-55.9%) in 3LOT. Median OS from 1LOT in favourable, intermediate and poor MSKCC were 39.7, 15.8 and 6.1 months respectively.. In this study, treatment was consistent with current National Institute for Health and Care Excellence (NICE) guidelines for mRCC patients. Although the study population favoured poorer prognosis patients, outcomes were more favourable than those for England at the same time. However, overall survival in this 'real-world' population remains poor and indicates significant unmet need for effective and safe treatment options to improve survival among mRCC patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Longitudinal Studies; Male; Middle Aged; Molecular Targeted Therapy; Practice Patterns, Physicians'; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; United Kingdom; Young Adult

First-line treatment for metastatic clear-cell renal cell carcinoma patients with intermediate and poor-risk features consists of a combination of immune checkpoint inhibitors (e.g., nivolumab + ipilimumab) or immunotherapy with an anti-vascular endothelial growth factor receptor (VEGFR) drug (e.g., axitinib). The subsequent line of therapy should be determined on the basis of previous treatments and approved drugs available, based on the results of randomized clinical trials. Unfortunately, no phase 3 trial has compared the safety and efficacy of drugs after immunotherapy; thus, drug choice is more empirical than evidence-based. As the tumor may still be anti-VEGFR drug-naïve, a tyrosine kinase inhibitor approved for first line treatment (e.g., sunitinib or pazopanib) may be beneficial. Because this is a second-line treatment, patients could also receive axitinib, cabozantinib, or a combination of lenvatinib and everolimus. The treating physician should choose an appropriate treatment according to the patient's age, comorbidities, and tolerability of previous checkpoint inhibitors, among other considerations. Cases of patients with renal cell carcinoma refractory to checkpoint inhibitor treatment are growing, warranting a review of the activity and safety of target therapies after immunotherapy.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Immunotherapy; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Nivolumab; Patient Selection; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Sulfonamides; Sunitinib

Pazopanib, a tyrosine kinase inhibitor, has been a standard first-line treatment for metastatic renal cell carcinoma (mRCC). Recent trials combining pazopanib with programmed cell death protein 1 (PD-1) inhibitors, including pembrolizumab, have shown excessive hepatotoxicity. We report a case of fatal hepatotoxicity from vanishing bile duct syndrome (VBDS) associated with pazopanib treatment, in a patient previously exposed to pembrolizumab. This is the first report of pazopanib-induced VBDS. We postulate whether prior exposure to pembrolizumab predisposed towards pazopanib-induction of VBDS, and discuss potential risks of sequential PD-1 inhibitor followed by pazopanib in mRCC, due to prolonged half-lives of PD-1 inhibitors.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Bile Duct Diseases; Bile Ducts, Intrahepatic; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides; Syndrome

Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib.. mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared.. Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017).. Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Chemokine CXCL12; Disease Progression; Drug Resistance, Neoplasm; E-Selectin; Female; Hepatocyte Growth Factor; Humans; Indazoles; Interleukin-6; Interleukin-8; Kidney Neoplasms; Male; Middle Aged; Osteopontin; Progression-Free Survival; Prospective Studies; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Sulfonamides; Survival Rate; Translational Research, Biomedical; Vascular Endothelial Growth Factor A

Clear-cell renal cell carcinomas (ccRCC) can be divided into four transcriptomic subtypes, two of which have a favorable and two an unfavorable prognosis. To assess mechanisms driving these subtypes, we investigated their miRNA expression patterns. miRNAs are master regulators of mRNAs, that are widely deregulated in cancer. Unsupervised clustering in our dataset (n = 128) and The Cancer Genome Atlas (TCGA) validation set identified two distinct miRNA clusters that overlapped with the transcriptomic subtypes, underscoring the validity of these subtypes on a multi-omics level and suggesting a driving role for miRNAs. Discriminatory miRNAs for the favorable subtypes repressed epithelial-to-mesenchymal transition, based on gene set enrichment analysis and target-mRNA expression levels. Strikingly, throughout the entire dataset, miRNAs associated with favorable subtypes were also associated with longer overall survival after diagnosis, and miRNAs associated with unfavorable subtypes with shorter overall survival (Pearson r = -0.54, p<0.0001). These findings indicate a general shift in miRNA expression between more and less aggressive tumors. This adds to current literature, which usually suggests only a small subset of miRNAs as markers of aggressive disease. In conclusion, this study reveals distinct mRNA expression patterns underlying transcriptomic ccRCC-subtypes, whereby miRNAs associated with favorable subtypes counteract epithelial-to-mesenchymal transition. There is a general shift in miRNA expression in ccRCC, between more and less aggressive tumors.

Topics: Carcinoma, Renal Cell; Female; Gene Expression Profiling; Humans; Indazoles; Kidney Neoplasms; Male; MicroRNAs; Middle Aged; Pyrimidines; RNA, Messenger; Sulfonamides; Sunitinib; Survival Analysis

To assess the cost-effectiveness of pazopanib versus sunitinib as a first-line treatment for patients with metastatic renal cell carcinoma (mRCC) from an Italian National Health Service perspective, considering the evolving Italian landscape in terms of new reimbursement agreements trend.. This analysis is an update of the previously published cost-effectiveness analysis to incorporate recent 2019 costs and additional changes regarding drug discounting. A partitioned-survival analysis model with three different health states (progression-free survival, post-progression survival, and dead) was utilized. Outcomes included progression-free life years, post-progression life years, overall life years, quality-adjusted life years (QALYs), and costs calculated for both treatments. Cost-effectiveness was assessed in terms of incremental costs per QALY gained and the net monetary benefit (NMB) of pazopanib versus sunitinib. In the base case analysis, a time horizon of 5 years was used and future costs and QALYs were discounted at a 3% annual discount rate. An impact of methodological and parameter uncertainly on base case results was evaluated using probabilistic and deterministic sensitivity analyses.. In the base case, pazopanib had higher QALYs (+0.060) at lower costs (-€5,857) versus sunitinib, hence it dominated sunitinib. At willingness-to-pay thresholds of €30,000 and €50,000 per QALY, the NMB with pazopanib were €7,647 and €8,841 per patient, respectively, versus sunitinib. The probability that pazopanib is cost-effective versus sunitinib was estimated to be 97.5% at a cost-effectiveness threshold of €20,000, 95.4% at a threshold of €30,000, and 90.2% at a threshold of €50,000 per QALY. Cost-effectiveness results were robust to changes in key parameter values and assumptions as demonstrated by deterministic sensitivity analyses.. Pazopanib is likely to represent a cost-effective treatment option compared with sunitinib as a first-line treatment for patients with metastatic RCC in Italy.

Topics: Carcinoma, Renal Cell; Cost-Benefit Analysis; Humans; Indazoles; Italy; Kidney Neoplasms; Pyrimidines; Quality-Adjusted Life Years; State Medicine; Sulfonamides; Sunitinib

Renal cell carcinoma (RCC) metastasis to the bladder is rare. We report two cases that occurred metachronously during pazopanib treatment for other metastases. To our knowledge, this is the first report to demonstrate bladder metastasis from RCC during molecular targeted therapy with pazopanib. (Case 1) A woman in her 60s was referred to our department for evaluation of an incidental right renal tumor. Dynamic CT showed a 6 cm renal cell carcinoma. In February 201X she underwent laparoscopic right radical nephrectomy, revealing clear cell carcinoma (grade 1>2), stage pT3aN0M0. In February 201X+1 she complained of left pelvic pain. She was found to have metastasis to two iliac bones and an occipital bone. She received pazopanib, in addition to a bone modifying agent and radiotherapy for the iliac bones. After 8 months, she complained of asymptomatic gross hematuria in spite of having stable disease for bone metastasis. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor on the posterior wall. She underwent transurethral resection of bladder tumor (TUR-BT). Histological examination showed metastatic RCC. Thereafter she received sequential therapies (axitinib, sunitinib, nivolumab). She remains alive without recurrence in the bladder 51 months after TUR-BT. (Case 2) A woman in her 60s presented to our department with a complaint of painless gross hematuria. A dynamic CT showed an 8.5 cm renal cell carcinoma and multiple lung metastases. In March 201Y she underwent right radical nephrectomy, revealing clear cell carcinoma (grade 2>3), stage pT2aN0M1. In June 201Y she started pazopanib. After 9 months CT showed a bladder tumor in addition to progression of lung metastases. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor at dome. She underwent TUR-BT. Histological examination showed metastatic RCC. She had no recurrence in the bladder during follow-up although she died of RCC.

Topics: Aged; Carcinoma, Renal Cell; Combined Modality Therapy; Cystectomy; Fatal Outcome; Female; Humans; Indazoles; Kidney Neoplasms; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Staging; Nephrectomy; Pyrimidines; Sulfonamides; Treatment Outcome; Urinary Bladder Neoplasms

The objective of this study is to describe the use of targeted therapies for the treatment of advanced renal cell carcinoma (RCC) and overall survival (OS) among patients in clinical practice in the Veterans Health Administration (VHA).. A retrospective cohort of 286 patients from 24 VHA Medical Centers diagnosed with advanced clear cell RCC between Fiscal Year (FY) 2010 and FY2014 was followed through September 30, 2016. Among patients who received targeted therapy, we described the medications taken, duration of therapy, and overall survival. We also assessed the effect of the first therapy received on overall survival using Cox Proportional Hazards models.. There were 66 patients who did not receive therapy for their advanced RCC. Of the 220 treated patients, the mean (sd) number of medications received was 1.9 (1.1). The medications most commonly used first were sunitinib (61.8%), pazopanib (17.3%), and temsirolimus (10.9%). The median duration of first-line therapy was 86 days (interquartile range [IQR] 42, 210). Median total duration of therapy was 159 days (IQR 58, 397). 62.3% of patients had ≥ 1 dose of therapy held or reduced, mainly due to an adverse drug event (ADE). Median survival from the start of treatment to death was 1.08 years (IQR 0.80, 1.31). Finally, receipt of temsirolimus vs sunitinib (HR 1.95 [95%CI 1.09,3.47]) as the first targeted therapy was independently associated with an increased hazard of death.. Our analysis of targeted therapies for advanced RCC in VHA suggests duration of treatment is shorter in a real-world setting than in clinical trials, and dose reductions and ADEs are more common.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; United States; United States Department of Veterans Affairs

Patients with metastatic renal carcinoma frequently have pre-existing renal impairment and not infrequently develop worsening renal function as a complication of their treatment. The presence of pancreatic metastases in patients with metastatic renal carcinoma, often confers a more favourable prognosis and as a consequence this patient group may be exposed to such treatments for more prolonged periods of time. However, the development of renal failure may also be a consequence of the cancer itself rather than its treatment.. We present an 84-year-old patient receiving the tyrosine kinase inhibitor (TKI) pazopanib for metastatic renal carcinoma who developed oxalate nephropathy as a consequence of pancreatic exocrine insufficiency resulting from pancreatic metastases.. This case demonstrates the importance of investigating unexpected toxicities and highlights the potential consequences of pancreatic insufficiency and its sequelae in patients with pancreatic metastases.

Topics: Acetates; Aged, 80 and over; Calcium Compounds; Carcinoma, Renal Cell; Exocrine Pancreatic Insufficiency; Gastrointestinal Agents; Humans; Indazoles; Kidney Failure, Chronic; Kidney Neoplasms; Male; Oxalates; Pancreatic Neoplasms; Pancrelipase; Protein Kinase Inhibitors; Pyrimidines; Renal Dialysis; Sulfonamides; Treatment Outcome

Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC).. A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized.. A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6 years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800 mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2 months. The median time on treatment was 10.0 months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9 months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%).. Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib.. Novartis Pharmaceuticals Corporation, Inc.

Topics: Aged; Carcinoma, Renal Cell; Disease Progression; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Latin America; Male; Middle Aged; Neoplasm Metastasis; Practice Patterns, Physicians'; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Time-to-Treatment

Topics: Carcinoma, Renal Cell; Eyelashes; Female; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Pigmentation Disorders; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines.. Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring.. Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy's law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing.. In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indazoles; Liver; Male; Middle Aged; Practice Patterns, Physicians'; Pyrimidines; Retrospective Studies; Sulfonamides

Topics: Carcinoma, Renal Cell; Female; Hair; Hair Color; Hair Diseases; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Pigmentation Disorders; Pyrimidines; Sulfonamides

To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis.. Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy.. Sixty-three patients were included in this study. At start of targeted therapy, 30% of patients were eugonadal and 48% had secondary hypogonadism. Decreased TT- and increased LH-levels were associated with inflammatory state and poor prognosis. During sunitinib therapy, TT-levels decreased with 32% (p = 0.004) and LH-levels with 14% (p = 0.03). TT-levels were 13% lower (p = 0.007) and LH-levels 15% lower (p = 0.004) on day 28 compared to day 1. In four patients, a dramatic TT decrease was observed shortly after starting sunitinib. In patients treated with pazopanib, no impact on TT- or LH-levels was observed.. Hypogonadism is a frequent finding in male mRCC-patients at start of targeted therapies. In contrast to pazopanib, during sunitinib therapy, TT- and LH-levels tend to decrease, leading to an increased incidence of secondary hypogonadism.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cross-Sectional Studies; Humans; Hypogonadism; Indazoles; Kidney Neoplasms; Luteinizing Hormone; Male; Middle Aged; Molecular Targeted Therapy; Prevalence; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib; Testosterone; Vascular Endothelial Growth Factor A

To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme.. Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.. A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7-6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus.. The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Immunological; Bone Neoplasms; Brain Neoplasms; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Progression-Free Survival; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Retreatment; Sulfonamides; Sunitinib; Survival Rate

About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination.. We conducted a multicenter retrospective study among centers from the French Groupe d'Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study.. A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination.. The incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Carcinoma, Renal Cell; Denosumab; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Humans; Hypocalcemia; Indazoles; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Indazoles; Kidney; Kidney Neoplasms; Necrosis; Neoadjuvant Therapy; Neoplasm Invasiveness; Nephrectomy; Nivolumab; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome; Vena Cava, Inferior

Severe adverse events frequently occur in patients treated with pazopanib, necessitating dose reduction and discontinuation. However, information on the exposure-toxicity relationship is limited.. For this retrospective and observational clinical study, we examined 27 patients with renal cell carcinoma treated with pazopanib and enrolled between October 2014 and March 2018. The primary goal was to evaluate the association between trough pazopanib concentration and occurrence of grade ≥ 3 toxicities, and secondarily, to estimate the association between trough pazopanib concentration and objective response rate.. Mean trough pazopanib concentration was significantly higher in the grade ≥ 3 toxicity group (n = 9) than in the grade ≤ 2 toxicity group (n = 18). Based on the receiver operating characteristic curve, the threshold value of trough pazopanib concentration for predicting grade ≥ 3 toxicities was 50.3 μg/mL (area under the curve, 0.85; 95% confidence interval, 0.70-0.99; P < .05). In the pazopanib < 20.5 μg/mL group (n = 3), no patient experienced an objective response. Objective response rates between patients with 20.5 to 50.3 μg/mL pazopanib (n = 11) and patients with ≥ 50.3 μg/mL (n = 13) were similar (45.5% vs. 46.2%).. From results of this study, the target trough pazopanib concentration range may be 20.5 to 50.3 μg/mL for patients with renal cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; ROC Curve; Sulfonamides; Survival Analysis; Treatment Outcome

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naïve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.. Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.. Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (≥6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade ≥3.. This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.

Topics: Adult; Aged; Anilides; Antineoplastic Agents, Immunological; Axitinib; Carcinoma, Renal Cell; Female; Humans; Indazoles; Ipilimumab; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Sunitinib; Treatment Failure

To evaluate whether sunitinib and pazopanib treatments are associated with change in skeletal muscle area (SMA) and total lean body mass (LBM) as well as to compare their efficacies and safety profiles in patients with metastatic renal cell cancer (mRCC).. Thirty-six patients treated with a tyrosine kinase inhibitor were included. Eighteen of them received sunitinib and the rest/remaining received pazopanib in the first line of mRCC treatment. Baseline and follow-up computed tomography studies of the patients were performed to measure cross-sectional areas (cm. About 69% of patients were male and median age was 60 (49-68) years. Median time interval between two CT imagings was 6.1 (3.1-7.7) months and it was similar between the two groups (for sunitinib, 4.9 (2.5-6.9) months vs for pazopanib, 7.3 (3.2-9.5) months, p = 0.16, respectively). Disease control rate was 77.7% in all patients. Of these, 66.6% in sunitinib group was consisted of four partial responses and eight stable diseases. In addition, 88.8% in pazopanib group was consisted of three partial responses and 13 stable diseases. A significant decrease in SMA and LBM was observed after sunitinib therapy, whereas SMA and LBM values of pazopanib group did not change significantly (p = 0.02 and p = 0.70, respectively). No significant differences were observed between patients with sunitinib, and pazopanib group median PFS [11.9 (95% CI 6.1-17.6) vs 8.1 months (95% CI 7.2-9.1), respectively; p = 0.28] and median OS [28.6 (95% CI 24.3-32.9) vs 25.5 months (95% CI 18.9-52.7), respectively; p = 0.42]. Dose-limiting toxicities were significantly more frequent in sunitinib group than in pazopanib group (66.7% vs 22.2%, p = 0.02, respectively).. Loss of SMA and LBM with sunitinib was more substantial than with pazopanib. Treatment efficacies of both drugs were similar, but dose-limiting toxicity was more frequent in sunitinib group. Loss of SMA had no significant association with prognosis. Further studies are needed to clarify the possible association between SMA and prognosis in mRCC patients who receive sunitinib or pazopanib.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Muscle, Skeletal; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Tomography, X-Ray Computed; Treatment Outcome

Nomograms have been developed for the prediction of progression-free survival (PFS) and liver toxicity in patients with advanced renal cell carcinoma (RCC) who are treated with pazopanib. The objectives of this study were to review clinical outcomes, to perform an external validation of these nomograms and to develop a new nomogram in Japanese patients.. A retrospective chart review of 150 Japanese patients with advanced RCC who received pazopanib at Kobe University Hospital and affiliated hospitals from March 2014 to June 2017 was performed. We evaluated the clinical efficacy and safety of pazopanib using logistic regression analysis to analyze the prognostic factors for overall survival (OS) and PFS. For nomogram validation, concordance index (C-index) and calibration were used.. The median PFS and OS in this study was 13.1 and 37.4 months, respectively. Multivariate analyses identified prognostic factors for OS (number of metastasis, white blood cell (WBC) count and lactate dehydrogenase) and PFS (number of metastasis, WBC count). The C-index of nomograms for 12-month PFS was 0.598. The C-index of nomograms for liver toxicity was 0.558. A new Nomogram for predicting 12-month PFS for patients who received pazopanib was developed and performed internal validation. The C-index of the nomogram was 0.768.. The clinical effect and safety of pazopanib reported in this study was similar to previous studies. This study suggests careful application of nomograms to Japanese patients treated with pazopanib. We have developed a new nomogram for predicting 12-month PFS with pazopanib therapy from Japanese patients.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Nomograms; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Rate

Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).. Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups.. Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2-12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups.. PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Prognosis; Prospective Studies; Pyrimidines; Quality of Life; Sulfonamides; Survival Rate; Treatment Outcome; Young Adult

Ultrasound microvessel imaging (UMI), when applied with ultrafast planewave acquisitions, has demonstrated superior blood signal sensitivity in comparison to conventional Doppler imaging. Here we propose a high spatial resolution and ultra-sensitive UMI that is based on conventional line-by-line high-frequency ultrasound imagers and singular value decomposition (SVD) clutter filtering for the visualization and quantification of tumor microvasculature and perfusion. The technique was applied to a chicken embryo tumor model of renal cell carcinoma that was treated with two FDA-approved anti-angiogenic agents at clinically relevant dosages. We demonstrate the feasibility of 3D evaluation with UMI to achieve highly sensitive detection of microvasculature using conventional line-by-line ultrasound imaging on a preclinical and commercially available high-frequency ultrasound device without software or hardware modifications. Quantitative parameters (vascularization index and fractional moving blood volume) derived from UMI images provide significantly improved evaluation of anti-angiogenic therapy response as compared with conventional power Doppler imaging, using histological analysis and immunohistochemistry as the reference standard. This proof-of-concept study demonstrates that high-frequency UMI is a low-cost, contrast-agent-free, easily applicable, accessible, and quantitative imaging tool for tumor characterization, which may be very useful for preclinical evaluation and longitudinal monitoring of anti-cancer treatment.

Topics: Angiogenesis Inhibitors; Animals; Blood Flow Velocity; Carcinoma, Renal Cell; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Contrast Media; Humans; Image Interpretation, Computer-Assisted; Indazoles; Kidney Neoplasms; Microvessels; Models, Biological; Neovascularization, Pathologic; Phantoms, Imaging; Proof of Concept Study; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Sunitinib; Ultrasonography

Patients in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk group have heterogeneous prognoses and thus may benefit from improved risk stratification.. The aim of this study was to analyze inflammatory parameters such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers for IMDC intermediate-risk patients.. Patients with metastatic clear cell renal cell carcinoma (n = 71) with IMDC intermediate risk who received tyrosine kinase inhibitors as first-line therapy were included in this retrospective study. Multivariate Cox regression analyses were performed to identify prognostic factors for overall survival (OS).. As first-line systemic therapy, 46 (65%), 19 (27%), and 6 (8%) patients received sunitinib, sorafenib, and pazopanib, respectively. An IMDC prognostic score of 1 and 2 were observed in 34 (48%) and 37 (52%) patients, respectively. Mean CRP level was 1.06 mg/dL, and mean NLR was 3.0. Multivariate Cox regression revealed several factors significantly associated with poor OS, including NLR ≥ 3 (vs NLR < 3; hazard ratio [HR] 2.57; p = 0.0228), CRP level ≥ 1 mg/dL (vs CRP < 1 mg/dL; HR 2.89; p = 0.0279), and two or more metastatic organs (vs one organ; HR 3.77; p = 0.0008). Using these risk factors, patients were stratified into the following three risk categories: F0 (no prognostic factors; n = 20), in which the median OS (mOS) was not achieved; F1 (1 prognostic factor; n = 31), in which the mOS was 31 months; and F2-3 (2 or 3 prognostic factors; n = 20) in which the mOS was 13 months (log-rank p < 0.0001).. CRP, NLR, and the number of metastatic organs were independent prognostic factors in IMDC intermediate-risk patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; C-Reactive Protein; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Lymphatic Metastasis; Lymphocytes; Male; Molecular Targeted Therapy; Neutrophils; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Assessment; Sorafenib; Sulfonamides; Sunitinib; Survival Rate

Tyrosine kinase inhibitors (TKIs) can cause cardiotoxicity, and some suggest routine monitoring of cardiac function during TKI use. We describe two cases of TKI-induced heart failure (HF) that suggest the utility of monitoring with laboratory tests is questionable. One patient developed HF 5 days after starting pazopanib. The other developed HF while receiving 25 mg per day sunitinib, and had previously received a higher dose (50 mg per day) with no symptoms of cardiotoxicy. In addition, she later received 5 cycles of sunitinib (25 mg per day) without developing an abnormal left ventricular ejection fraction (LVEF) value by echocardiography or cardiac symptoms. Although the LVEF is commonly performed to monitor TKI cardiotoxicity, evidence for its predictive utility is limited. These cases raise questions regarding the practical utility of sequential measurement of LVEF in adults treated with TKIs. We suggest a simple daily activity such as stair climbing to monitor exercise tolerance.

Topics: Aged; Carcinoma, Renal Cell; Female; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Leiomyosarcoma; Middle Aged; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Sunitinib

Elderly metastatic renal cell carcinoma (mRCC) patients are under-represented in clinical trials, whose results are therefore difficult to translate into routine management of older patients. We aimed at exploring treatment outcomes and prognostic factors in our real-life elderly mRCC cohort receiving first-line tyrosine kinase inhibitor (TKI) monotherapy.. We retrospectively analyzed demographic and clinicopathological characteristics, and treatment data of elderly (≥ 70 years old at first-line start) mRCC patients starting either pazopanib or sunitinib as first-line treatment in our institution between March 2012 and April 2018. Baseline characteristics included age-adjusted Charlson comorbidity index (CCI).. In total, the records of 35 elderly mRCC patients were identified and retrospectively analyzed. Overall response rate, median progression-free survival, and median overall survival were 20%, 9.7 months, and 21.6 months, respectively. Karnofsky performance status ≤ 70%, sarcomatoid features, absolute neutrophil count greater than upper limit of normal, and treatment-related Grade 3 arterial hypertension were independently associated with survival after multivariate analysis. Age-adjusted CCI was significantly associated with survival in univariate analysis only. The overall incidence of Grade 3 to 5 toxicities was 74%. Seven patients (20%) received early crossover to either sunitinib or pazopanib because of toxicity. Dose reduction was applied in 24 (73%) of the 33 patients who completed at least 1 cycle.. First-line TKI monotherapy provided clinical benefit in our elderly mRCC cohort. Relatively frequent dose reductions helped to maintain an acceptable tolerability profile. Further research is warranted to explore the significance of prognostic factors in elderly mRCC patients.

Topics: Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Multivariate Analysis; Neoplasm Metastasis; Outcome Assessment, Health Care; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; United Kingdom

We report a case of a patient with renal cell carcinoma on pazopanib, who presented with severe upper gastrointestinal bleeding. Endoscopy showed a giant bulbar ulcer with a visible vessel of 4 mm. Due to unavailability of surgical rescue backup, large calibre vessel treatment was delayed. Endoscopy was repeated after 48 hours and showed a reduction in the vessel diameter. Endoscopic adrenalin injection and electrocoagulation were performed. However, the vessel increased in size and became pulsatile. The patient was operated, confirming a giant bulbar ulcer penetrating the pancreas with active bleeding from the gastroduodenal artery. Pazopanib therapy was suspended, and the patient is asymptomatic. Antiangiogenic treatment has been associated with gastrointestinal bleeding, perforation and fistulisation. Although we cannot confirm the causal association between the penetrating ulcer and pazopanib, the absence of

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Duodenal Ulcer; Electrocoagulation; Endoscopy; Gastrointestinal Hemorrhage; Gastroplasty; Humans; Indazoles; Melena; Middle Aged; Pancreas; Proton Pump Inhibitors; Pylorus; Pyrimidines; Sulfonamides; Syncope; Treatment Outcome

Mucositis is often experienced in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies. This might impair daily quality of life and lead to dose reduction, discontinuation, or treatment shift. We assessed the effect of folic acid to reduce mucositis.. Patients treated with systemic therapy for mRCC who developed Grade ≥2 mucositis according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) received oral folic acid to reduce mucositis. The medical charts were retrospectively reviewed.. A total of 77 patients had Grade ≥2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-α (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months.. Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Everolimus; Female; Folic Acid; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Treatment Outcome

The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778).. Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients.. Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS ≥ 2 (vs. PS < 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar.. Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs. ≥ 2) to more accurately predict outcomes.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Patient Safety; Prognosis; Prospective Studies; Pyrimidines; Risk Factors; Sulfonamides; Survival Rate; Young Adult

Recent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.. Patients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.. In total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.. In accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Molecular Targeted Therapy; Precision Medicine; Pyrimidines; Sulfonamides; Survival Analysis; Treatment Outcome

Treatment decisions in routine clinical practice are based on reports of clinical trials, which represent highly selected populations. Limited studies reported real-world evidences representing routine clinical practices in patients with renal-cell carcinoma (RCC) in Europe. The aim of this retrospective, noninterventional chart review was to collect data on the treatment landscape for patients with advanced/metastatic RCC in routine clinical practice in a broader patient population in Austria.. Patients with advanced/metastatic RCC receiving systemic treatment between June 2010 and June 2016 across 12 centers in Austria were included. Parameters were entered into an electronic case report form from the participating sites via the application Hermesoft electronic data capture system. Progression-free survival (PFS) and overall survival (OS) were the 2 primary end points.. The median PFS and OS were 12 months and 44 months, respectively (first-line PFS was 14 months for pazopanib and 13 months for sunitinib; first-line OS was 44 months for pazopanib and 48 months for sunitinib). Factors influencing the OS were sex, with female patients at a significantly higher risk than male patients (hazard ratio = 1.719), Eastern Cooperative Oncology Group performance status > 0 increased the risk twice (hazard ratio = 2.048), and number of metastases > 3 before the first line doubled the risk compared to metastases (hazard ratio = 2.064).. OS in this retrospective chart review was considerably longer than the previous reports in real-world patients, underlining the benefit of current RCC treatment options in routine clinical practice.

Topics: Aged; Antineoplastic Agents; Austria; Carcinoma, Renal Cell; Clinical Decision-Making; Electronic Health Records; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sex Characteristics; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

Stereotactic ablative radiotherapy (SAbR) is a promising alternative for selected patients with renal cell carcinoma (RCC) with oligometastasis. The objective of this study was to evaluate the potential of SAbR for longitudinal control in patients with persistently oligometastatic RCC. We report the impact of SAbR on tumor control rates as well as its tolerability in systemic therapy-naïve patients with oligometastatic disease (without brain metastases) and assess the effect of SAbR on subsequent first line systemic therapy by comparison to historical controls.. We reviewed patients with metastatic RCC treated with front-line SAbR with a curative intent from 2007 to 2017 at UT Southwestern Kidney Cancer Program. We analyzed local control rates (LCR), toxicity, freedom from systemic therapy (FST), type and duration of first-line systemic therapy, and overall survival (OS). Cox regression and Kaplan-Meier analyses were used.. We identified 47 patients with oligometastatic RCC treated with SAbR to 88 metastases; 11 patients had more than 1 SAbR course. The local control rate was 91.5% at 2 years with no reported grade ≥3 toxicity. With a median follow-up of 30 months (interquartile range, 13.7-40.9), median FST from first SAbR was 15.2 months (95% confidence interval [CI], 8.8-40.1). The most common systemic therapies initiated after SAbR were pazopanib (60.7%) and sunitinib (14.3%). The duration of first line systemic therapy appeared unaffected by SAbR. Improved FST was observed in patients with metachronous disease (hazard ratio, 2.67; P = .02), solitary metastasis (HR, 2.26; P = .05), and non-bone metastasis (HR, 2.21; P = .04). One-year and 2-year OS after SAbR were 93.1% (95% CI, 80.1-97.7) and 84.8% (95% CI, 69.1-92.9), respectively. Median OS was not reached.. SAbR is an effective and safe treatment for selected patients with oligometastatic RCC, can provide longitudinal disease control without systemic therapy for over a year, and does not appear to adversely affect the effectiveness of first-line systemic therapy once initiated. Prospective validation of these findings is being sought through a phase 2 trial.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Confidence Intervals; Female; Follow-Up Studies; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Pyrimidines; Quality of Life; Radiosurgery; Regression Analysis; Retrospective Studies; Sulfonamides; Sunitinib; Survival Rate; Tomography, X-Ray Computed

In the setting of metastatic RCC (mRCC), pazopanib is approved as first line therapy. Unfortunately treatment may lead to cardiotoxicity such as hypertension, heart failure, and myocardial ischemia.. Define the in vivo role of pazopanib in the development of cardiotoxicity.. Wild type mice were dosed for 42 days via oral gavage, and separated into control and treatment (pazopanib) groups. Baseline ECG's, echocardiograms, and blood pressures were recorded. At the conclusion of the study functional parameters were again recorded, and animals were used for pathological, histological, and protein analysis.. After 2 weeks of dosing with pazopanib, the treatment group exhibited a statistically significant increase in mean arterial pressure compared to control mice (119 ± 11.7 mmHg versus 108 ± 8.2 mmHg, p = 0.049). Treatment with pazopanib led to a significant reduction in the cardiac output of mice.. Our findings in mice clearly demonstrate that treatment with pazopanib leads to a significant elevation in blood pressure after 2 weeks of dosing and this persists for the duration of dosing. The continued development of the cardio-oncology field will be paramount in providing optimal oncologic care while simultaneously improving cardiac outcomes through further investigation into the mechanisms of CV toxicity.

Topics: Angiogenesis Inhibitors; Animals; Arterial Pressure; Body Weight; Carcinoma, Renal Cell; Cardiac Output; Disease Models, Animal; Echocardiography; Electrocardiography; Heart; Hypertension; Indazoles; Kidney; Kidney Neoplasms; Mice; Myocardium; Pyrimidines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sulfonamides; Vascular Endothelial Growth Factor A

High out-of-pocket costs may limit access to oral therapies covered by patients' prescription drug benefits. We explored financial barriers to treatment initiation in patients newly diagnosed with metastatic renal cell carcinoma (mRCC) by comparing Medicare Part D patients with low out-of-pocket costs due to receipt of full low-income subsidies (LIS beneficiaries) to their counterparts who were responsible for more than 25% cost sharing during Medicare's initial coverage phase (non-LIS beneficiaries). We used 2011-2013 100% Medicare claims for non-LIS and LIS beneficiaries newly diagnosed with metastases in the liver, lung, or bone to examine targeted therapy treatment initiation rates and time to initiation for (1) oral medications (sorafenib, sunitinib, everolimus, pazopanib, or axitinib) covered under Medicare's prescription drug benefit (Part D); (2) injected or infused medications (temsirolimus or bevacizumab) covered by Medicare's medical benefit (Part B); and (3) any (Part D or Part B) targeted therapy. The final sample included 1721 patients. On average, non-LIS patients were responsible for out-of-pocket costs of ≥$2,800 for their initial oral prescription, as compared to ≤$6.60 for LIS patients. Compared to LIS patients, a lower percentage of non-LIS patients initiated oral therapies (risk-adjusted rates, 20.7% vs. 33.9%; odds ratio [OR] = 0.49, 95% CI: 0.36-0.67, P < 0.001) and any targeted therapies (26.7% vs. 40.4%, OR = 0.52, 95% CI: 0.38-0.71, P < 0.001). Non-LIS patients were also slower to access therapy. High cost sharing was associated with reduced and/or delayed access to targeted therapies under Medicare Part D, suggesting that financial barriers play a role in treatment decisions.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Decision-Making; Cost Sharing; Female; Health Expenditures; Health Services Accessibility; Humans; Indazoles; Kidney Neoplasms; Medicare Part D; Molecular Targeted Therapy; Patient Selection; Poverty; Pyrimidines; Retrospective Studies; Sulfonamides; Time Factors; United States

We previously described 4 molecular subtypes of metastatic clear cell renal cell carcinoma (mccRCC), named ccrcc1-4 (Beuselinck et al, 2015). These have both prognostic and predictive value for patients treated with first-line sunitinib, with distinctive objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The ccrcc2 and ccrcc3 tumors have the best outcomes, followed by ccrcc1 and then ccrcc4. We hypothesized that these molecular subtypes would show similar outcomes with first-line pazopanib treatment.. We classified 28 mccRCC tumors treated with pazopanib as first-line therapy, as described previously. The primary endpoints were PFS and OS from the start of pazopanib. A secondary endpoint was ORR. Because there were only 2 ccrcc3 tumors, they were pooled with the ccrcc2 tumors for outcome analysis.. PFS was 9 months for the ccrcc2 and ccrcc3 tumors, 5 months for ccrcc1 tumors, and 3 months for the ccrcc4 tumors (P = .011). The corresponding OS duration was 69, 19, and 5 months (P = .003). The corresponding ORR was 50%, 33%, and 0%. The corresponding mean tumor size decreased by 34%, 6%, and 2% (P = .032). The ccrcc1-4 classification was a stronger predictor of outcome than the International Metastatic Renal Cell Carcinoma Database Consortium score on univariate analysis (P = .011 vs. P = .094 for PFS and P = .003 vs. .013 for OS). Both remained independent on bivariate analysis.. The molecular subtypes of mccRCC are associated with outcome on pazopanib as first-line therapy. The prognostic and predictive value of the ccrcc1-4 molecular classification requires validation in prospective trials.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Prospective Studies; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome

To test the hypothesis that cytoreductive nephrectomy (CN) improves overall survival (OS) of patients with synchronous metastatic renal cell carcinoma (mRCC), who subsequently receive targeted therapies (TT).. We identified 261 patients who received TT for synchronous mRCC with or without prior CN. To achieve balance in baseline characteristics between groups, we used the inverse probability of treatment weighting (IPTW) method. We conducted OS analyses, including IPTW-adjusted Kaplan-Meier curves, Cox regression models, interaction term, and landmark and sensitivity analyses.. Of the 261 patients, 97 (37.2%) received CN and 164 (62.8%) did not. IPTW-adjusted analyses showed a statistically significant OS benefit for patients treated with CN (HR 0.63, 95% CI 0.46-0.83, P = 0.0015). While there was no statistically significant difference in OS at 3 months (P = 0.97), 6 months (P = 0.67), and 12 months (P = 0.11) from diagnosis, a benefit for the CN group was noted at 18 months (P = 0.005) and 24 months (P = 0.004). On interaction term analyses, the beneficial effect of CN increased with better performance status (P = 0.06), in women (P = 0.03), and in patients with thrombocytosis (P = 0.01).. IPTW-adjusted analysis of our patient cohort suggests that CN improves OS of patients with synchronous mRCC treated with TT. On the whole, the survival difference appears after 12 months. Specific subgroups may particularly benefit from CN, and these subgroups warrant further investigation in prospective trials.

Topics: Aged; Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Nephrectomy; Nivolumab; Probability; Prognosis; Proportional Hazards Models; Pyridines; Pyrimidines; Pyrroles; Retrospective Studies; Sex Factors; Sulfonamides; Sunitinib; Survival Rate; Thrombocytosis

Pazopanib is approved for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). The present study was a retrospective registry-based analysis of 426 patients with mRCC treated with pazopanib as first-line targeted therapy.. The data were obtained from the Renal Cell Carcinoma Information system registry. Patient baseline parameters, treatment course and outcomes, and toxicity were analysed.. Median progression-free and overall survival were 12.9 (95% confidence interval(CI)=11.0-14.8) months and 33.2 (95% CI=29.9-36.4) months, respectively. Overall response rate and disease control rate were 25.1% and 57.4%, respectively. Adverse events led to discontinuation of treatment in 37 (12.1%) patients.. The results confirm that pazopanib is an effective and safe first-line targeted treatment in patients with mRCC. Both the International mRCC Database Consortium and the Memorial Sloan Kettering models were valid predictors of prognosis and nephrectomy was associated with improved survival.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Czech Republic; Databases, Factual; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Proto-Oncogene Proteins c-kit; Pyrimidines; Pyrroles; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Registries; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome

Topics: Angiogenesis Inhibitors; Atrial Flutter; Carcinoma, Renal Cell; Electrocardiography; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides

Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FE

Topics: Administration, Oral; Aged; Carcinoma, Renal Cell; Cohort Studies; Denmark; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Hospitals, University; Humans; Hypertension; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Nitric Oxide; Prospective Studies; Pyrimidines; Risk Assessment; Sulfonamides; Time Factors

Topics: Aged; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Drug Synergism; Humans; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Nivolumab; Pyrimidines; Sulfonamides; Treatment Outcome

Von Hippel-Lindau (VHL) disease is a multisystem genetic disease, the cardinal manifestations of which include central nervous system hemangioblastomas (CNS HB), renal cell carcinomas (RCC), and pheochromocytoma. Tumorigenesis in VHL of both RCC and CNS HB occurs secondary to downstream effects of a mutated or absent VHL protein. Treatment of RCCs with tyrosine kinase inhibitors (TKIs) such as Pazopanib is now first line therapy, but their effect on VHL-associated CNS HBs remains unknown. We report the use of Pazopanib in a patient with VHL disease for treatment of RCC who also harbored multiple CNS HBs. Following initiation of treatment, a large cervical and a lumbar spinal HB regressed in size while the remaining CNS HBs exhibited stable or progressive disease. These findings highlight the multiplicity of factors contributing to hemangioblastoma development, even among tumors with a common germline mutation, and the potential limitations of TKIs, but additionally this report supports the conservative management of asymptomatic VHL patients with spinal HBs whereby tumor response to TKI treatment may alleviate or postpone the need for surgery.

Topics: Adult; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Central Nervous System Neoplasms; Hemangioblastoma; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides; von Hippel-Lindau Disease

Introduction Tumor lysis syndrome (TLS) is a life-threatening emergency caused by rapid cell death as a result of anti-tumor therapy. In the era of targeted therapy it has increasingly been observed in solid malignancies such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Case We describe the case of a 58-year old man with the medical history of a memorial sloan kettering cancer centre (MSKCC) poor prognosis metastasized clear cell renal cell carcinoma (mRCC) who developed TLS within six days after initiating therapy with the tyrosine kinase inhibitor (TKI) pazopanib. Discussion The pharmacokinetics and pharmacodynamics of pazopanib are complex and characterized by a non-linear and time-dependent bioavailability. Pazopanib is almost completely bound to serum albumin (>99.9%). In this presented case, a low serum albumin (26 g/L) might have led to a higher free fraction of pazopanib, which could have resulted in more toxicity. Also, pazopanib is metabolised by the CYP3A4 isoform of the cytochrome P450 group. Low quantities of this enzyme may lead to an impaired and prolonged breakdown of the drug. Conclusion As far as we know this is the first report on pazopanib induced TLS. We advise further research in order to identify the exact mechanism behind TKI-induced TLS and the patients at risk of developing TLS.

Topics: Carcinoma, Renal Cell; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Patient Admission; Pyrimidines; Sulfonamides; Tumor Lysis Syndrome

Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown.. In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety.. The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups.. Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid-reducing therapy.. Pazopanib is a preferred category-one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Cohort Studies; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Analysis

Higher concentrations of TKIs, such as pazopanib, are associated with improved outcomes in advanced RCC. A phase III trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome

The aim of this study was to investigate the clinical benefit of presurgical therapy with pazopanib in renal cell carcinoma (RCC) patients with a tumor thrombus extending to a high level in the vena cava. A retrospective review was performed for seven consecutive patients with RCC and tumor thrombus involving the vena cava above the hepatic vein (level 3-4, Mayo Clinic classification) treated with pazopanib without initial cytoreductive nephrectomy at our institution. The effect of pazopanib was assessed in terms of the primary site response, thrombus diameter, and height (before and after treatment) on computed tomography or MRI. The tumor thrombus level before the induction of pazopanib was 3 in one patient and 4 in the remaining six patients. After pazopanib, shrinkage of the primary site and thrombus diameter and length were observed in all patients except one (with a rhabdoid tumor). The mean decreases of primary tumor diameter, tumor thrombus diameter, and length were 14, 9, and 31 mm, respectively. The tumor thrombus level decreased in three (43%) patients and remained stable in the remaining patient. Our findings suggest that presurgical treatment with pazopanib may shrink the tumor thrombus and decrease the surgical invasiveness in RCC patients with a high-level tumor thrombus.

Topics: Aged; Aged, 80 and over; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Pyrimidines; Retrospective Studies; Sulfonamides; Vena Cava, Inferior; Venous Thrombosis

Pazopanib is among the current standards of care for first-line treatment of patients with unresectable advanced renal-cell carcinoma (aRCC) or metastatic renal-cell carcinoma. This real-world study aimed to characterize those with long-term response to pazopanib in the treatment of aRCC in a community oncology setting, and to identify predictors of long-term response.. aRCC patients treated with first-line pazopanib were classified as having long-term or non-long-term response (progression-free survival [PFS] of ≥ 18 or < 18 months, respectively). Baseline patient demographics and clinical characteristics were evaluated and compared between the 2 groups. Differences in PFS and overall survival were also evaluated.. A total of 153 eligible patients were identified, of which 33 (21.6%) and 120 (78.4%) patients were identified as having disease with long-term and non-long-term response, respectively. The median PFS for those with long-term response was 27.2 months (95% confidence interval [CI], 23.0-35.2) versus 6.9 months (95% CI, 5.0-8.6) for those with non-long-term response. Median overall survival was not reached (NR) for those with long-term response (95% CI, NR to 39.1) compared to 15.3 months (95% CI, 12.3-21.6) for those with non-long-term response. Baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 (vs. ECOG PS of 1 and ≥ 2) and history of nephrectomy were identified as significant predictors of long-term response to pazopanib.. In aRCC patients treated with first-line pazopanib, 22% had a long-term response. Significant predictors of long-term response included an ECOG PS of 0 and a history of nephrectomy.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Logistic Models; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome; Young Adult

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/β-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4

Topics: B7-H1 Antigen; beta Catenin; Biomarkers; Carcinoma, Renal Cell; Cell Line, Tumor; Cytokines; Dendritic Cells; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Immunophenotyping; Indazoles; Kidney Neoplasms; Phagocytosis; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; Sulfonamides; T-Lymphocytes

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Radiosurgery; Sulfonamides

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Nephrectomy; Pyrimidines; Sulfonamides

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Kidney Neoplasms; Mice; Mice, SCID; Mice, Transgenic; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

The median age at renal cell carcinoma (RCC) diagnosis is 64 years. However, few studies have assessed the real-world time on treatment (TOT), health resource utilization (HRU), costs, or treatment compliance associated with targeted therapy use among patients in this age group with RCC.. To assess the HRU, costs, and compliance during TOT among Medicare patients aged ≥ 65 years with advanced RCC (aRCC) who initiated first targeted therapy with pazopanib or sunitinib.. Patients with aRCC were identified in the 100% Medicare + Part D databases administered by the Centers for Medicare & Medicaid Services. Eligible patients initiated first targeted therapy with sunitinib or pazopanib (index drug) on or after their first diagnosis of secondary neoplasm between October 19, 2009, and January 1, 2014, and were aged ≥ 65 years as of 1 year before first targeted therapy initiation (index date). Included patients were stratified into pazopanib and sunitinib cohorts based on first targeted therapy and matched 1:1 on baseline characteristics using propensity scores. TOT was defined as the time from the index date to treatment discontinuation (prescription gap > 90 days) or death. Compliance was defined as the ratio of drug supply days to TOT. Monthly all-cause costs and costs associated with RCC diagnosis (medical and pharmacy in 2015 U.S. dollars) and HRU (inpatient [admissions, readmissions, and days], outpatient, and emergency room visits) were assessed in the 1-year post-index period during TOT. Matched cohorts' TOT was compared using Kaplan-Meier analyses and univariable Cox models, and compliance, HRU, and costs were compared using Wilcoxon signed-rank tests.. Of 1,711 included patients, 526 initiated pazopanib and 1,185 initiated sunitinib. Before matching, more patients in the pazopanib cohort were white, diagnosed in 2010-2014 versus 2006-2009, and had lung metastases compared with the sunitinib cohort (all P < 0.05). The pazopanib cohort also had higher mean outpatient visits and costs but lower mean total all-cause pharmacy costs, than the sunitinib cohort (all P < 0.05). After matching, the pazopanib and sunitinib cohorts had similar characteristics (mean age 75 years, 58% male, and Charlson Comorbidity Index score of 9.2 in both cohorts) and median TOT (4.8 and 4.1 months, respectively). Among the 522 matched pairs, pazopanib was associated with significantly lower total all-cause health care costs ($8,527 vs. $10,924, respectively [mean difference = $2,397]); total medical costs ($3,991 vs. $5,881, respectively, [$1,890]); and inpatient costs ($2,040 vs. $3,731, respectively, [$1,692]; all P < 0.01) compared with sunitinib. Patients receiving pazopanib had significantly fewer inpatient admissions (0.179 vs. 0.289, respectively) and days (1.063 vs. 1.904, respectively; both P < 0.01) than patients receiving sunitinib. Mean treatment compliance was lower for the pazopanib versus sunitinib cohort (0.91 vs. 0.94, respectively; P < 0.01).. In this retrospective analysis of Medicare patients with aRCC from a TOT perspective, first targeted therapy with pazopanib was associated with significantly lower all-cause health care costs and HRU, but lower compliance, compared with sunitinib.. Funding for this research was provided by Novartis Pharmaceuticals. The sponsor was involved in all stages of the study's conduct and reporting. Vogelzang has been a consultant for Novartis, Amgen, Celgene, Medivation, Eisai, Exelixis, and Roche; has spoken at Novartis, Astellas, Johnson and Johnson, Pfizer, Dendreon, Bayer/Algeta, GSK, and Veridex/Janssen; and has received research support from Novartis, Bayer, Exelixis, Progenics, Bavarian Nordic, and Viamet. Pal has been a consultant for Novartis, Pfizer, Aveo, Dendreon, and Myriad and has spoken at Novartis, Pfizer and Medivation. Agarwal has been a consultant or advisor for Novartis, Pfizer, Exelixis, Cerulean Pharma, Medivation, Eisai, and Argos Therapeutics. Swallow, Peeples, Zichlin, and Meiselbach are employees of Analysis Group, which received consultancy fees from Novartis for this project. Li was an employee of Analysis Group during the conduct of this study. Ghate is an employee of Novartis and owns stock/stock options. Perez was an employee of Novartis during the conduct of this study. A synopsis of the economic outcomes was presented at the Academy of Managed Care Pharmacy Nexus 2017 in Denver, Colorado, during March 27-30, 2017. A synopsis of the clinical outcomes was presented at the 22nd ISPOR Annual International Meeting in Boston, Massachusetts, during May 20-24, 2017.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Health Care Costs; Health Resources; Humans; Indazoles; Indoles; Insurance Claim Review; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Medicare; Patient Acceptance of Health Care; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Time Factors; Treatment Outcome; United States

Pneumatosis cystoides intestinalis is characterized by multiple air-filled cysts in the intestine wall. A perforation causes pneumoperitoneum, frequently with minimal clinical affectation and do not require surgery at first in most cases. Recently, some cancer treatments, mainly molecular targeted therapy, have been associated with this complication. For this reason, radiologic findings of intestinal pneumatosis and/or secondary perforation during patient follow-up should be carefully interpreted. The clinical-analytical findings should always be considered. We report a case associated with the use of tyrosine kinase inhibitors in order to illustrate this point.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Male; Pneumatosis Cystoides Intestinalis; Pneumoperitoneum; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed

The specific characteristics of patients who are most likely to benefit from pazopanib therapy are still uncertain. We report on the results of an Italian multicenter, retrospective analysis investigating the factors associated with longer response to first-line pazopanib in patients with metastatic renal cell carcinoma.. Adult patients were considered if they had received treatment with pazopanib (800 mg/day) for >12 months in the first-line setting.. In total, 112 patients were evaluated. Median duration of pazopanib treatment was 22.6 months (IQR 17.8 months). Median PFS was 22.6 months (95%CI= 20.2-25.0). Eighty-three patients (74.1%) had a PFS ≥18 months. Median OS was 32.9 months (95%CI=30.2-35.6). At statistical analysis, only PS score (1+ vs. 0) was significantly associated with PFS (HR=1.76; 95%CI=1.02-3.05; p=0.04).. Pazopanib therapy may be suitable for all patients with mRCC, and especially in those with PS 0.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Italy; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sulfonamides

A 70-year-old man with history of stage IV renal cell carcinoma, chronic atrial fibrillation on warfarin, coronary artery disease status post-percutaneous coronary intervention resulting in an ischaemic cardiomyopathy with left ventricular ejection fraction of 40%-45%, presented with shortness of breath 10 days after starting pazopanib. Within the first week of starting pazopanib, the patient developed fatigue and progressive dyspnoea on exertion. His symptoms quickly worsened and he had compromised mental status. He was transferred to the intensive care unit (ICU) and intubated due to continued respiratory distress. He was found to be in cardiogenic shock and was started on inotropic support with dobutamine and norepinephrine. With maximum support, the patient was slowly weaned off vasopressors and was successfully extubated on ICU day 9. His hospital stay lasted 29 days with management of multiple medical complications, and he was eventually discharged to a rehabilitation facility.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

Purpose Sunitinib and pazopanib are multitargeted tyrosine kinase inhibitors (TKIs) that act against vascular endothelial growth factor receptors and are standard first-line treatment options for metastatic clear cell renal cell carcinoma (ccRCC). The Brazilian public health system diverges from the randomized clinical trials in the availability of first and subsequent lines of treatment and in clinical and demographic characteristics of patients. Therefore, it is essential to describe the history of advanced ccRCC during and after TKI treatment in this population. Methods We performed a retrospective analysis of patients with advanced ccRCC treated with a first-line TKI (either sunitinib or pazopanib) between February 2009 and March 2017 in a single academic Brazilian cancer center (Instituto do Câncer do Estado de São Paulo). Results Of the 222 patients, 109 were treated with sunitinib and 113 with pazopanib. The median duration of treatment and overall survival (OS) were 6.4 and 15.2 months for sunitinib and 6.7 and 14.2 months for pazopanib, respectively. Discontinuation of treatment occurred secondarily to progressive disease or death in 64.2% of patients using sunitinib and in 54.8% of patients using pazopanib. Adverse events were responsible for discontinuation of treatment in 28.4% of patients in the sunitinib group and in 22.1% in the pazopanib group. According to Memorial Sloan-Kettering Cancer Center risk categories, the OS was 32.9 months, 15.9 months, and 8.1 months for low risk, intermediate risk, and poor risk, respectively (hazard ratio, 1.72; 95% CI, 1.13 to 2.26; P < .001). Conclusion The use of TKI inhibitors as first-line treatment of metastatic RCC is effective and feasible in the Brazilian public health. However, the median OS of our population is considerably lower compared with the prospective trials that evaluated the same drugs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brazil; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; Young Adult

Autophagy has been shown to be involved in cancer development and response to cancer therapy. In this study, genotypes of autophagic genes were analyzed to assess their correlation with the risk of clear cell renal cell carcinoma (ccRCC) and the outcome of patients treated with pazopanib for metastatic ccRCC.. Single nucleotide polymorphisms (SNPs)were selected in the following genes: ATG4A (rs7880351), ATG4B (rs6709768), ATG4C (rs2886770, rs6670694, rs6683832), ATG5 (rs9373839, rs3804333, rs490010), ATG16L1 (rs6752107), ATG16L2 (rs10751215) and IRGM (rs10059011). The Kaplan-Meier method and log-rank test were used to evaluate differences between groups.. Forty patients with metastatic ccRCC treated with pazopanib were included in the analysis. ATG16L2rs10751215 was significantly less frequent in patients with ccRCC compared to the general population, suggesting its potential protective role, while ATG4Ars7880351, ATG4C rs6670694 and rs6683832 and ATG5 rs490010 were correlated with the progression-free survival (PFS) of patients treated with pazopanib.. Our results suggest, for the first time, that autophagic gene SNPs are associated with ccRCC risk and patient outcome.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Autophagy; Autophagy-Related Proteins; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Liquid Biopsy; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Polymorphism, Genetic; Prognosis; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Rate

To evaluate survival outcomes and prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who received sunitinib (SU) and pazopanib (PZ) as first-line therapy in real-world Korean clinical practice.. Data of 554 patients with mRCC who received SU or PZ at eight institutions between 2012 and 2016 were retrospectively reviewed. Based on the targeted therapy, the patients were divided into SU (n = 293) or PZ (n = 261) groups, and the clinicopathological variables and survival rates of the two groups were compared. A multivariable Cox proportional hazard model was used to determine the prognostic factors for OS.. The median follow-up was 16.4 months (interquartile range, 8.3-31.3). Patients in the PZ group were older, and no significant difference was observed in the performance status (PS) between the two groups. In the SU group, the dose reduction rate was higher and the incidence of grade 3 toxicity was more frequent. The objective response rates were comparable between the two groups (SU, 32.1% vs. PZ, 36.4%). OS did not differ significantly between the two groups (SU, 36.5 months vs. PZ, 40.2 months; log-rank,. Our real-world data of Korean patients with mRCC suggested that SU and PZ had similar efficacies as first-line therapy for mRCC. However, PZ was better tolerated than SU in Korean patients.

Topics: Aged; Bone Neoplasms; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Liver Neoplasms; Male; Middle Aged; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome

Topics: Angiogenesis Inhibitors; Anticoagulants; Arrhythmias, Cardiac; Carcinoma, Renal Cell; Female; Heart Neoplasms; Heparin; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Palliative Care; Pyrimidines; Radiography, Thoracic; Sulfonamides; Tricuspid Valve Insufficiency; Tumor Burden

For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort.. EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses.. In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy.. Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cohort Studies; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Young Adult

Topics: Carcinoma, Renal Cell; Drug Administration Schedule; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Paraneoplastic Syndromes; Pyrimidines; Stroke Volume; Sulfonamides; Treatment Outcome

Pazopanib is a tyrosine kinase receptor antagonist used for renal cell carcinoma and soft tissue sarcoma that inhibits tumour growth and angiogenesis. A common side effect of pazopanib is hypertension. We report a case of a 69-year-old woman with clear cell renal cell carcinoma who developed a large right occipital intracerebral haemorrhage 3 weeks after initiating pazopanib. Although this was initially suspected to be a haemorrhagic metastasis, MRI revealed bi-occipital oedema, supporting a diagnosis of posterior reversible encephalopathy syndrome (PRES). A craniectomy was required. Immunohistochemical stains for renal cell carcinoma antigen, CA IX and PAX8 were negative. This case suggests that PRES and intracerebral haemorrhage may result from pazopanib use and are important complications to consider prior to initiating this agent.

Topics: Aged; Carcinoma, Renal Cell; Cerebral Hemorrhage; Decompressive Craniectomy; Female; Humans; Indazoles; Kidney Neoplasms; Magnetic Resonance Imaging; Posterior Leukoencephalopathy Syndrome; Pyrimidines; Sulfonamides; Treatment Outcome

Pazopanib, one of the antiangiogenic drugs, has recently become a first-line treatment for metastatic renal cell carcinoma. The most common adverse effects of pazopanib include diarrhea, fatigue, and nausea, but neuropathic complication has not been documented. Here, we report the first case of a patient with metastatic renal cell carcinoma who developed acute neuropathy mimicking Guillain-Barré syndrome following the first course of pazopanib therapy. A 75-year-old man with a metastatic renal cell carcinoma was admitted for rapidly progressive weakness and numbness in the extremities after the first course of pazopanib therapy. Neurological examination revealed symmetrical distal limb weakness, sensory disturbance, and areflexia. Based on the clinical pictures, conduction slowing on the nerve conduction studies of the extremities and albuminocytologic dissociation on the cerebrospinal fluid examination, a diagnosis of Guillain-Barré syndrome was made. After discontinuation of pazopanib and a subsequent high-dose intravenous immunoglobulin therapy, symptoms rapidly resolved and the patient became ambulatory with a cane. Serological and neuroradiological examinations failed to reveal any possible causes for the neuropathy other than pazopanib. While the benefits of pazopanib for metastatic renal cell carcinoma far outweigh this neurotoxic effect, physicians prescribing this drug should be aware of this rare complication of neuropathy.

Topics: Administration, Oral; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Electromyography; Guillain-Barre Syndrome; Humans; Immunoglobulins, Intravenous; Indazoles; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Pyrimidines; Serologic Tests; Sulfonamides

VEGFR and mTOR inhibitors are broadly used in metastatic renal cell carcinoma (mRCC) therapy, and sequential first-line pazopanib (VEGFR inhibitor) and second-line everolimus (mTOR inhibitor) is a standard treatment option. Nivolumab and lenvatinib/everolimus combination was recently approved in Europe for use in mRCC after previous therapy. Prospective routine data on sequential therapy including nivolumab and/or lenvatinib are missing. This is a prospective, noninterventional study, which evaluates the effectiveness, tolerability, safety and quality of life following 450 patients with mRCC starting either on pazopanib as first-line therapy or third-line everolimus plus/minus lenvatinib following nivolumab. Adults with histologically confirmed mRCC of any subtype, who have a life expectancy of at least 6 months, are eligible.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Humans; Indazoles; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Nivolumab; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Sulfonamides; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor Receptor-1

Sunitinib and pazopanib are the only two targeted therapies for the first-line treatment of locally advanced or metastatic renal cell carcinoma (mRCC) recommended by the United Kingdom's National Institute for Health and Care Excellence. Pazopanib demonstrated non-inferior efficacy and a differentiated safety profile versus sunitinib in the phase III COMPARZ trial. The current analysis provides a direct comparison of the cost-effectiveness of pazopanib versus sunitinib from the perspective of the United Kingdom's National Health Service based on data from COMPARZ and other sources.. A partitioned-survival analysis model with three health states (alive with no progression, alive with progression, or dead) was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained for pazopanib versus sunitinib over five years (duration of follow-up for final survival analysis in COMPARZ). The proportion of patients in each health state over time was based on Kaplan-Meier distributions for progression-free and overall survival from COMPARZ. Utility values were based on EQ-5D data from the pivotal study of pazopanib versus placebo. Costs were based on medical resource utilisation data from COMPARZ and unit costs from secondary sources. Probabilistic and deterministic sensitivity analyses were conducted to assess uncertainty of model results.. In the base case, pazopanib was estimated to provide more QALYs (0.0565, 95% credible interval [CrI]: -0.0920 to 0.2126) at a lower cost (-£1,061, 95% CrI: -£4,328 to £2,067) versus sunitinib. The probability that pazopanib yields more QALYs than sunitinib was estimated to be 76%. For a threshold value of £30,000 per QALY gained, the probability that pazopanib is cost-effective versus sunitinib was estimated to be 95%. Pazopanib was dominant in most scenarios examined in deterministic sensitivity analyses.. Pazopanib is likely to be a cost-effective treatment option compared with sunitinib as first-line treatment of mRCC in the United Kingdom.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Markov Chains; Middle Aged; Prognosis; Pyrimidines; Pyrroles; Quality-Adjusted Life Years; Sulfonamides; Sunitinib; Survival Rate; United Kingdom

In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters.. Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment).. Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category.. A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cytokines; E-Selectin; Female; Hemoglobins; Hepatocyte Growth Factor; Humans; Indazoles; Interleukin-6; Interleukin-8; Kidney Neoplasms; L-Lactate Dehydrogenase; Leukocyte Count; Male; Middle Aged; Neutrophils; Osteopontin; Prognosis; Pyrimidines; Sulfonamides; Survival Rate; Time-to-Treatment; Tissue Inhibitor of Metalloproteinase-1; Tumor Burden; Vascular Endothelial Growth Factor A

Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long-term response to this treatment.. In a retrospective, registry-based study, patients continuously treated with first-line anti-VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis.. Median progression-free survival (PFS) after initiation of first-line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9-43.5 months), with 5-year PFS of 34.2% (95% CI, 27.2%-41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2-93.0 months) with the 5-year OS of 62.1% (95% CI, 54.5%-69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference < .001 and .009 for OS difference).. There are marked differences in PFS and OS between patients who receive long-term anti-VEGF treatment, achieving CR and non-CR as the best clinical response. Patients with non-CR experienced a relatively high progression rate shortly after the landmark time point of 2 years.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Registries; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; Vascular Endothelial Growth Factor A

Previous research has identified disparities between urban and rural cancer care, including clinical trial access. Therefore, we addressed three different questions in patients with metastatic renal cell cancer managed according to national guidelines in a rural Norwegian standard practice setting. (1) How many patients would have been eligible for three recent landmark randomized clinical trials? (2) Is survival different between eligible and non-eligible patients receiving first-line systemic therapy? (3) Is survival different between eligible patients and published trial results? We performed a retrospective analysis of 101 consecutive patients (2006-2016). Only 52% of the patients were eligible for the first-line study of pazopanib versus sunitinib. The main reasons for violating inclusion or exclusion criteria were presence of brain metastases, absence of clear cell histology, and poor performance status. Even fewer patients were eligible for trials of nivolumab and cabozantinib in pre-treated patients. Eligible patients had significantly better survival than non-eligible patients, median 29.2 versus 8.5 months (p = 0.0001). These results confirm that many patients from rural practices do not fulfill all mandatory trial eligibility criteria. However, eligible patients managed according to national guidelines had survival outcomes in line with published first-line trial results.

Topics: Aged; Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Pyridines; Pyrimidines; Pyrroles; Retrospective Studies; Rural Population; Sulfonamides; Sunitinib

The objective of this study was to describe treatment patterns, survival, healthcare use and costs in patients with metastatic renal cell carcinoma (mRCC) in a real-world setting.. We used the National Health Insurance (NHI) claims database for the Ile-de-France region to perform a retrospective cohort analysis of patients with mRCC treated by a first-line targeted therapy. Treatment naïve patients were identified combining the 10th revision of the International Classification of Diseases (ICD-10) codes (C64 & C77-C79) and a first prescription of targeted therapies. Descriptive analyses were performed on treatment patterns and patients' characteristics. Progression free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier actuarial survival analysis. All healthcare resource use and costs were estimated on a per patient per month (PPPM) basis (€2016).. A total of 327 treatment naïve patients with mRCC were included. Median follow-up was 13.4 months. Sunitinib accounted for 73% of first-line treatments. The most frequently observed treatment sequence for the first two lines was sunitinib-everolimus (16%; n = 137) and for the first three lines sunitinib-everolimus-axitinib (20%; n = 49). First-line PFS for sunitinib, everolimus, pazopanib, sorafenib and other was 8.7, 6.2, 10.7, 5.7 and 11.2 months, respectively. Median OS for patients treated by first-line sunitinib, everolimus, pazopanib, sorafenib and other was respectively 14.7, 8.1, 21.1, 8.9 and 14.0 months. From the NHI's perspective, the mean PPPM was €5546. The average PPPM in pre-progression was €5597 compared to €5541 beyond progression of the disease. Oral targeted therapies accounted for 53% of the total PPPM.. This descriptive study showed that the economic burden of mRCC is substantial with oral targeted therapies accounting for 53% of the PPPM. OS and PFS in real life are poorer than observed in clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Cohort Studies; Databases, Factual; Disease-Free Survival; Everolimus; Female; France; Humans; Imidazoles; Indazoles; Indoles; Insurance, Health; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib

Topics: Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides

Pazopanib is a standard treatment for metastatic renal cell carcinoma (mRCC), and 800 mg/daily is considered the optimal dose. However, some patients require dose modification because of toxicity. Whether a reduced dose of pazopanib is as effective as the standard dose in achieving clinical benefit remains unclear.. Our objective was to conduct a retrospective analysis to investigate the clinical effect of different therapeutic doses of first-line pazopanib in patients with mRCC.. Consecutive patients with mRCC treated with first-line pazopanib between 2011 and 2016 at the Istituto Nazionale Tumori of Milan were retrospectively analysed for demographics, response, outcomes, and toxicity. Three patient groups were compared: group 1 received the standard dose of 800 mg/day; group 2 started with 800 mg/day and then reduced the dose to 400 or 600 mg/day because of toxicity; and group 3 received a reduced starting dose of 400 or 600 mg/day because they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and/or comorbidities.. In total, 69 patients were evaluated: 34 in group 1, 19 in group 2, and 16 in group 3. After a median follow-up of 13.9 months (range 0.3-43.8), 27 (39.1%) patients had progressive disease (PD) and three (4.3%) patients had died. The incidence rate of PD or death per 100 person-months was 2.5 [95% confidence interval (CI) 0.6-4.4; hazard ratio (HR) 1] in group 1 and 3.9 (95% CI 0-14.3; HR 1.43) in the combined group (2 + 3). The discontinuation rate due to PD was 28% in group 1, 42% in group 2, and 44% in group 3. The objective response rate was 44, 11, and 19% in groups 1, 2, and 3, respectively.. Our results may suggest that patients with mRCC receiving a lower dose of first-line pazopanib might not have a meaningful progression-free survival advantage compared with those receiving a standard dose. These data highlight that proper management of treatment-related side effects may lead to optimal drug exposure.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome

A 63-year-old man presented with a pulsatile cutaneous horn on the nose and multiple angiomatous nodules on the gingiva and scalp, which appeared over 2 months. He had severe hypercalcaemia, lytic lesions in multiple bones and acute kidney injury. Excision biopsy from the gingival nodule showed a clear cell neoplasm. The bone marrow showed atypical cells with similar morphology. Imaging showed a 7 cmx7.5 cm mass at the upper pole of the left kidney with metastases to the bones, liver and lung. Immunohistochemistry was consistent with metastatic renal cell carcinoma. Renal cell carcinoma presenting as a cutaneous horn is extremely rare and to the best of our knowledge only one other case was found in the literature. There was visible regression in the size of the cutaneous horn and nodules following initiation of pazopanib therapy. However, he succumbed to his illness a month later.

Topics: Acute Kidney Injury; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Diagnosis, Differential; Fatal Outcome; Gingiva; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Scalp; Skin Neoplasms; Sulfonamides

The purpose of this study is to compare the prognostic value of various solid tumor response criteria as well as the additive value of clinical risk factors in patients with advanced renal cell carcinoma (RCC).. Two sets of CT scans (pretreatment scans and scans obtained 1-3.5 months after treatment) were reviewed for 57 patients with metastatic RCC treated with pazopanib in the salvage setting. Tumor response on the posttherapy scan was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) and Choi, modified Choi (mChoi), MASS (Morphology, Attenuation, Size, and Structure), and 10% threshold criteria. In addition, combined Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors plus imaging criteria were used to define response groups. Response evaluations using these criteria were correlated with overall survival (OS) and progression-free survival (PFS), with use of the log-rank test.. Patients classified as having progressive disease (PD) on the basis of RECIST, mChoi, and MASS criteria had a significantly worse OS than patients with stable disease (SD) and partial response (PR). With the addition of MSKCC risk factors, all groups with PD defined by combined criteria had significantly worse OS. For 37 patients with no or one MSKCC risk factor, response groups defined by Choi, mChoi, MASS, and 10% threshold criteria did not differ in PFS or OS. However, among 20 patients with two to three MSKCC risk factors, those classified as having PR had longer PFS than did those with SD and had longer OS than did those with PD.. For patients with advanced RCC for which prior therapies have failed, the prognostic value of various imaging-based tumor response criteria differs on the basis of the MSKCC clinical risk status.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Contrast Media; Disease Progression; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Risk Factors; Salvage Therapy; Sulfonamides; Tomography, X-Ray Computed

Limited data about biomarkers are available to predict the outcomes of targeted therapy in metastatic renal cell carcinoma (mRCC). Circulating cell-free DNA (CFD) is elevated in various cancers.. We performed a prospective study of patients with mRCC who received targeted therapy in the Soroka Medical Center between 2013 and 2015. CFD levels were measured using a simple fluorometric assay. Blood samples for CFD were collected before treatment and at weeks 1, 4, 12, 18, and 24 of treatment. The normal cut-off level of CFD was defined as 800 ng/ml. The association of CFD with objective response, progression-free survival (PFS), and overall survival was tested, with adjustment for known confounding risk factors.. A total of 23 patients were included; 18 were treated with first-line therapy and 5 with second- and third-line therapies. Patients with normal pretreatment CFD level had a better PFS versus patients with increased levels (p = 0.023). In multivariate analysis, factors associated with PFS were pretreatment CFD levels (p = 0.020) and Heng risk (p = 0.006).. Elevated pretreatment CFD levels measured using a simple fluorometric assay may be associated with a worse PFS in patients with mRCC. A larger prospective study is warranted in order to validate our observation.

Topics: Aged; Aged, 80 and over; Axitinib; Carcinoma, Renal Cell; Cell-Free Nucleic Acids; Combined Modality Therapy; Disease-Free Survival; Everolimus; Female; Follow-Up Studies; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Predictive Value of Tests; Prospective Studies; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Neoplasm Recurrence, Local; Nephrectomy; Pyrimidines; Sulfonamides

Studies indicate similar survival and toxicity between pazopanib and sunitinib, but few have examined real-world outcomes among elderly patients with advanced renal cell carcinoma (RCC). The purpose of this retrospective claims analysis was to assess real-world overall survival (OS), healthcare resource utilization (HRU), and healthcare costs (both all-cause and associated with RCC diagnosis) among elderly advanced RCC patients starting pazopanib or sunitinib treatment.. Advanced RCC patients aged 65 years or older who started first-line treatment with pazopanib or sunitinib (index drug; the initiation date was the index date) were identified from the 100% Medicare database plus Part D linkage (January 1, 2006 to December 31, 2014). Patients were stratified by index drug and matched 1:1 with use of propensity scores based on baseline characteristics. OS was assessed from the index date to death and compared by Kaplan-Meier analyses and univariable Cox models; patients were censored at the end of eligibility/data. Monthly HRU and costs from an intent-to-treat perspective were compared by Wilcoxon signed-rank tests.. Baseline characteristics were balanced after matching (both N = 522). Treatment with pazopanib was associated with significantly longer median OS compared with treatment with sunitinib (18.2 months vs 14.6 months, respectively; log-rank p = 0.015). Pazopanib was associated with significantly lower monthly all-cause costs compared with sunitinib ($8845 vs $10,416, respectively), as well as lower inpatient costs associated with RCC diagnosis ($1542 vs $2522), fewer monthly inpatient admissions (0.179 vs 0.262), and shorter length of inpatient stay (1.375 days vs 1.883 days; all p ≤ 0.004).. Among elderly Medicare patients with advanced RCC, first-line pazopanib tretament was associated with significantly longer OS, as well as lower healthcare costs and HRU, compared with first-line sunitinib treatment.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Databases, Factual; Female; Health Expenditures; Humans; Indazoles; Indoles; Insurance Claim Review; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Medicare; Middle Aged; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; United States

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Leg Ulcer; Male; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Sorafenib; Sulfonamides

A 73-year-old male with a remote history of renal cell carcinoma presented with an asymptomatic left ventricular mass. Biopsy of the mass revealed a late recurrence of his renal cell carcinoma. Given the size and location of the mass, resection was not possible. Treatment with pazopanib was initiated with good clinical response.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Heart Neoplasms; Heart Ventricles; Humans; Indazoles; Kidney Neoplasms; Male; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Topics: Adolescent; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Drug Eruptions; Fatal Outcome; Female; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Topics: Carcinoma, Renal Cell; Exome Sequencing; Female; Fumarate Hydratase; GRB2 Adaptor Protein; Humans; Indazoles; Indoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Treatment Outcome; Young Adult

To evaluate the association between the timing of best tumor shrinkage (bTS) and metastatic renal cell carcinoma (mRCC) patient survival after first-line tyrosine kinase inhibitor (TKI) therapy.. The tumors of 91 patients with mRCC showed a response to TKIs. None of the patients had received prior cytokine therapy. The magnitude of bTS was categorized according to the Response Evaluation Criteria in Solid Tumors v. 1.1. The patients were divided into two subgroups according to the timing of bTS: early responders (≤3 months) and late responders (>3 months). Overall survival (OS) and progression-free survival (PFS) after first-line TKI therapy were evaluated, and factors predicting survival were examined.. Sunitinib, sorafenib, and pazopanib were used in 62, 25, and 4 responders, respectively. In total, 52 (57.1 %) and 39 (42.9 %) patients were early and late responders, respectively. Early responders had significantly lower PFS compared to late responders (median survival, 11.4 vs. 19.1 months; log-rank test, p = 0.0263), although there were no significant differences in the OS of early and late responders (27.0 vs. 30.1 months, p = 0.306). Multivariate analyses revealed that the timing of bTS was an independent predictor of PFS and OS (PFS, hazard ratio 4.09, p < 0.0001; OS, hazard ratio 2.32, p = 0.0107).. The timing of bTS was an independent predictor of survival in patients with mRCC who received first-line TKIs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Response Evaluation Criteria in Solid Tumors; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; Time Factors

Pazopanib is associated with increased progression-free survival (PFS) in clear-cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non-clear-cell RCC, but data on outcomes in this setting are limited.. We conducted a retrospective data analysis of records of consecutive metastatic non-clear-cell RCC patients who received pazopanib in front-line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan-Meier methods.. Twenty-nine patients were identified with non-clear-cell metastatic RCC, 9 received pazopanib in the front-line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7-NA [not available]) in the front-line group, and 4 months (95% CI, 2.1-9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2-NA) in the front-line group, and 13.6 months (95% CI, 6.4-NA) in the salvage group.. Pazopanib showed efficacy in patients with metastatic non-clear-cell RCC in the front-line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanib's role in non-clear-cell RCC in terms of efficacy and safety.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Analysis; Treatment Outcome; Young Adult

Given the variability in drug levels with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC), dose escalation at the occurrence of progressive disease (PD) might have antitumor effects.. The data from patients with mRCC who were treated at the Cleveland Clinic with TKIs and received a dose escalation after PD in accordance with Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, were retrospectively reviewed. Patient- and disease-related data were collected and summarized as frequency counts and percentages or medians and ranges. The Kaplan-Meier method was used to summarize the treatment duration for the escalated doses.. Twenty-two patients were identified. Most patients (82%) were men; the median age at diagnosis was 58 years (range, 40-71 years). The most common histologic type was clear cell (73%). Axitinib was the most frequently escalated agent after PD (17 patients), followed by sunitinib (3 patients), and pazopanib (2 patients). Before PD, the median treatment duration was 6.8 months (range, 1.6-50.6 months). Of the 18 patients with evaluable tumor measurements after dose escalation, 14 (78%) had a decrease in tumor burden. The median decrease in tumor burden after dose escalation was 14% (range, 2%-58%); 4 patients (22%) had decreases ≥10%, 2 (11%) ≥20%, and 4 (22%) >30% (RECIST partial response). At the last follow-up examination, 5 patients (23%) continued to be treated at escalated doses. The median duration of escalated therapy was estimated at 10.1 months (range, 0.6 to 37.9 months).. Dose escalation of TKIs after PD for select patients with mRCC can lead to a reduction in tumor burden and extend the duration of therapy.

Topics: Adult; Aged; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; Tumor Burden

Tyrosine kinase inhibitor-related toxicities have been reported to be predictive and/or prognostic factors in patients affected by metastatic renal cell carcinoma (mRCC). We aim to investigate the incidence of cumulative toxicity and its prognostic role in mRCC patients treated with sunitinib or pazopanib. mRCC patients treated with sunitinib or pazopanib at the European Institute of Oncology in Milan were reviewed for the incidence of adverse events. Cumulative toxicity was defined as the presence of more than one selected adverse event of any grade. Prognoses were evaluated by the International mRCC Database Consortium criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and Cox analysis. A total of 104 patients were included in the final analysis. Only 18.3% did not experience any of the selected toxicities: 26.9% had one, 35.6% had two and 19.2% all three toxicities. Accordingly, 54.8% of patients experienced cumulative toxicity. In those with or without cumulative toxicity, the median PFS was 27.6 versus 7.2 months and the median OS was 61.2 versus 18.7 months, respectively. When cumulative toxicity was adjusted for International mRCC Database Consortium prognostic groups, it maintained its prognostic role for both PFS (hazard ratio: 0.31, 95% confidence interval, 0.20-0.49; P<0.001) and OS (hazard ratio: 0.27, 95% confidence interval, 0.15-0.48; P<0.001). A major limitation was the retrospective and monocentric nature of the analysis. We reported the prognostic role of cumulative toxicity because of hypertension, hypothyroidism and hand-foot syndrome in patients affected by mRCC and treated with sunitinib or pazopanib.

Topics: Aged; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Survival Rate

Topics: Adult; Aged; Carcinoma, Renal Cell; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indazoles; Kidney Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Unknown Primary; Pyrimidines; Sensitivity and Specificity; Sulfonamides; Treatment Outcome

Research suggests that baseline use of angiotensin system inhibitors (ASIs) improves outcome in patients with metastatic renal cell carcinoma (mRCC), but it remains unknown whether the type of antihypertensive medication used to initiate management at onset of treatment-induced hypertension (HTN) is associated with outcome. We evaluated the association of ASIs and outcome among patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs).. We identified 303 consecutive patients with mRCC who were treated with sunitinib or pazopanib in a single university hospital cancer center. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for known risk factors.. Progression-free survival (PFS) and overall survival (OS) were similar among patients with baseline HTN (n = 197; 65%) versus patients with no baseline HTN (n = 106; 35%) (PFS; P = .72) (OS; P = .54). There was a significant difference between patients with treatment-induced HTN (n = 110) versus patients with no treatment-induced HTN (n = 193) for PFS (15.6 vs. 6.4 months, respectively; P < .001) and OS (34.9 vs. 13.9 months, respectively; P < .001). Use of ASIs at baseline (n = 126; 41.6%) had no impact on outcome as compared with patients receiving other antihypertensive medication (n = 71; 23.4%) or with patients with no baseline antihypertensive medication (n = 106; 35.0%). Among patients with TKI-induced HTN (n = 110), however, ASI users (n = 91) demonstrated improved OS (37.5 vs. 18.1 months; P = .001) and PFS (17.1 vs. 7.2 months; P = .004) versus ASI nonusers (n = 19), respectively.. Our results demonstrate survival benefit for ASI users among patients with TKI-induced HTN. These results, however, require further validation in a prospective setting.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Carcinoma, Renal Cell; Female; Humans; Hypertension; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; Young Adult

The real-world survival outcomes and prognostic factors among patients receiving first-line targeted therapy for advanced renal cell carcinoma (aRCC) are not well known.. Adult patients diagnosed with RCC and treated with first-line targeted therapy were identified from the Surveillance, Epidemiology, and End Results-Medicare database (January 1, 1993 to December 31, 2012). The patients were grouped into early (2006-2009) or late (2010-2012) targeted therapy era cohorts by the year of the first-line targeted therapy initiation. Overall survival (OS) was measured from first-line targeted therapy initiation and compared between the 2 cohorts using Kaplan-Meier analyses. The prognostic factors for OS were assessed using a multivariable-adjusted Cox model.. A total of 604 and 641 aRCC patients (mean age, 68 years; ∼60% male in both cohorts) initiated first-line targeted therapy during the early and late targeted therapy eras, respectively. OS was significantly longer in the late than in the early targeted therapy era. Higher tumor grades (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.31-2.00) and lung (HR, 1.27; 95% CI, 1.06-1.53), bone (HR, 1.37; 95% CI, 1.13-1.66), and liver (HR, 1.42; 95% CI, 1.10-1.84) metastases were associated with significantly shorter OS. Previous nephrectomy (HR, 0.55; 95% CI, 0.42-0.72) and pazopanib as first-line targeted therapy relative to sorafenib (HR, 0.56; 95% CI, 0.37-0.85) or sunitinib (HR, 0.65; 95% CI, 0.44-0.95) were associated with significantly longer OS.. The results of these real-world analyses suggest progress in aRCC management and identified positive (nephrectomy, pazopanib vs. sunitinib or sorafenib) and negative (higher tumor grade and lung, bone, or liver metastasis) prognostic factors among patients receiving first-line targeted therapy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Grading; Nephrectomy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; SEER Program; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

A prior randomized controlled trial (COMPARZ [Comparing the Efficacy, Safety and Tolerability of Pazopanib versus Sunitinib]) found non-inferior progression-free survival for pazopanib versus sunitinib as first-line therapy in patients with advanced or metastatic renal cell carcinoma. The present study evaluated the cost-effectiveness of pazopanib versus sunitinib as first-line treatment for patients with metastatic renal cell carcinoma from an Italian National Health Service perspective.. A partitioned-survival analysis model with 3 health states (progression-free survival, post-progression survival, and dead) was employed. The model time horizon was 5 years. For each treatment strategy, the model generated expected progression-free life years, post-progression life years, overall life years, quality-adjusted life years (QALYs), and costs. Results were reported as incremental costs per QALY gained and the net monetary benefit of pazopanib versus sunitinib. Probabilistic and deterministic sensitivity analyses were conducted to assess the impact on results of methodological and parameter uncertainty.. In the base case, pazopanib was associated with higher QALYs and lower costs and dominated sunitinib. Using willingness-to-pay thresholds of €30,000 and €50,000 per QALY, the net monetary benefits with pazopanib were €6508 and €7702 per patient, respectively, versus sunitinib. The probability that pazopanib is cost-effective versus sunitinib was estimated to be 85% at a cost-effectiveness threshold of €20,000, 86% at a threshold of €30,000, and 81% at a threshold of €50,000 per QALY. Results were robust to changes in key parameter values and assumptions.. These results suggest that pazopanib is likely to represent a cost-effective treatment option compared with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma in Italy.

Topics: Carcinoma, Renal Cell; Cost-Benefit Analysis; Disease-Free Survival; Humans; Indazoles; Indoles; Italy; Kidney Neoplasms; National Health Programs; Pyrimidines; Pyrroles; Quality-Adjusted Life Years; Sulfonamides; Sunitinib; Survival Analysis

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Sunitinib

To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma.. A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ. Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor.. The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.

Topics: Aged; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Disease Progression; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Nephrectomy; Practice Guidelines as Topic; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

The aim of this study was to evaluate the prognostic value of pretreatment metabolic tumor volume (MTV) and total lesion glycolysis (TLG) using F-FDG PET/CT in patients with metastatic renal cell carcinoma (RCC) after treatment with anti-vascular endothelial growth factor-targeted agents.. Fifty-six patients with metastatic RCC who underwent F-FDG PET/CT for staging and recurrence evaluation were retrospectively enrolled. SUVmax, MTV, and TLG were measured using F-FDG PET/CT in all patients. The highest SUV in all the metastatic RCC lesions of each patient was defined as SUVmax. Metabolic tumor volume was defined as the total tumor volume greater than 40% of SUVmax. Total lesion glycolysis was calculated as (MTV) · (SUVmean). The prognostic significance of PET/CT parameters and clinical factors for progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analyses, along with other clinical factors.. The most common organ for metastases was lung (35 patients). In the univariate analysis, hypercalcemia, time from diagnosis to treatment, SUVmax, MTV, and TLG were significant prognostic factors affecting PFS (P < 0.05), and Karnofsky score, hypercalcemia, time from diagnosis to treatment, SUVmax, MTV, and TLG were significant prognostic factors affecting OS (P < 0.05). In the multivariate analysis, hypercalcemia, MTV, and TLG were independent prognostic factors affecting PFS (P < 0.05), and hypercalcemia, time from diagnosis to treatment, MTV, and TLG were independent prognostic factors affecting OS (P < 0.05). In subgroup analyses, the high MTV or TLG groups showed poor prognosis for PFS and OS in patients with intermediate or poor risk.. Metabolic tumor volume and TLG are independent prognostic factors for predicting PFS and OS in patients with metastatic RCC. Furthermore, MTV and TLG could provide additional prognostic information in patients with clinically high-risk metastatic RCC treated with anti-vascular endothelial growth factor-targeted therapies.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Female; Fluorodeoxyglucose F18; Glycolysis; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Positron Emission Tomography Computed Tomography; Pyrimidines; Pyrroles; Radiopharmaceuticals; Sorafenib; Sulfonamides; Sunitinib

Pazopanib is a potent multitargeted tyrosine kinase inhibitor that has been shown to have good efficacy in patients with renal cell carcinoma. A previous phase II trial demonstrated that short-term pazopanib administration was generally well tolerated and showed antitumor activity in patients with early-stage non-small cell lung cancer. Herein, we report on the case of a 66-year-old man with simultaneous metastatic squamous cell carcinoma of the lung and renal cell carcinoma who was treated with pazopanib. The patient showed an unexpected partial response and experienced a 10-month progression-free survival without significant toxicity. To the best of the authors' knowledge, this is the first report of pazopanib treatment in a non-small cell lung cancer patient in Korea. The results in this patient suggest that pazopanib may be a valid treatment option for advanced non-small cell lung cancer.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Lung Neoplasms; Male; Protein-Tyrosine Kinases; Pyrimidines; Republic of Korea; Sulfonamides; Treatment Outcome

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs.. Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment.. Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9±3.8% at T0, -17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped.. All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs.

Topics: Aged; Antineoplastic Agents; Arteries; Blood Pressure; Carcinoma, Renal Cell; Female; Heart; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pulse Wave Analysis; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib; Thyroid Neoplasms; Vascular Stiffness

To identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment.. A retrospective review of patients with mRCC in an outpatient clinic was carried out for the period January 2006 to November 2011. Patient characteristics, including demographics, laboratory data and outcomes, were analysed. Baseline characteristics were compared using chi-squared and t-tests and overall survival (OS) and cancer-specific survival (CSS) rates were estimated using Kaplan-Meier methods. Predictors of OS were analysed using Cox regression.. A total of 228 patients were reviewed, of whom 44 (19.3%) had PM and 184 (81.7%) had metastases to sites other than the pancreas. The distribution of baseline characteristics was equal in both groups, with the exception of a higher incidence of previous nephrectomy, diabetes and number of metastatic sites in the PM group. Four patients had isolated PM, but the majority of patients (68%) with PM had at least three different organ sites of metastases, as compared with 29% in patients without PM (P < 0.01). The distribution of organ sites of metastases was similar, excluding the pancreas, in those with and those without PM (P > 0.05). The median OS was 39 months (95% confidence interval [CI] 24-57, hazard ratio 0.66, 95% CI 0.42-0.94; P = 0.02) for patients with PM, compared with 26 months (95% CI 21-31) for patients without PM (P < 0.01). CSS was 42 months (95% CI 30-57) in the PM group and 27 months (95% CI 22-33) in the control group (P = 0.05).. Despite a higher number of affected organ sites in the PM cohort, mRCC behaviour in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumour features associated with PM may represent a less aggressive tumour phenotype.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Proportional Hazards Models; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Survival Rate; Treatment Outcome

The aim of the RECCORD registry was to gather real-world UK data on the use of targeted therapies in renal cell carcinoma (RCC) and assess clinical outcomes. Here, demographic and outcome data are presented with the treatment patterns and demographic profile of patients on the registry.. Patients were retrospectively identified at seven UK hospitals with large cancer centres in England (5), Scotland (1) and Wales (1). Anonymised data were collected through an online registry covering demographics, treatments and outcomes. Five hundred and fourteen UK adult patients with metastatic RCC were included in the study for analysis. Patients were included if they were treated for metastatic RCC at one of the seven centres, and started systemic anti-cancer treatment from March 2009 to November 2012 inclusive. In addition to demographic factors, the principal outcome measures were overall survival (OS), time to disease progression and toxicity.. The majority of first-line treatment was with sunitinib; first-line use of pazopanib increased as the study progressed. 15.8% of patients received second-line treatment, half of whom were prescribed everolimus. Median OS (from initiation of first-line treatment) was 23.9 months (95% confidence interval [CI] 18.6-29.1 months), similar to that reported for clinical trials of targeted RCC therapies [Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615-621; Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013; 20: 944-955; Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590]. OS was significantly longer for those who received second-line treatment after disease progression (33.0 months; 95% CI 30.8-35.2 months) than those who did not (20.9 months; 95% CI 16.4-25.3 months; P = 0.008).. RECCORD is a large 'real-world' database assessing metastatic RCC treatment patterns and outcomes. Treatment patterns changed over time as targeted therapies were approved and became widely available; survival data in RECCORD are consistent with those reported for systemic treatments in clinical trials. Kaplan-Meier analysis of results demonstrated that receiving second-line therapy was a major prognostic factor for longer OS.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Female; Humans; Indazoles; Indoles; Interferon-alpha; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Pyrroles; Registries; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; United Kingdom

Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies.. The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks.. Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age ≥60 years, a glomerular filtration rate (GFR) <30 mL/min/1.73 m(2) , a single metastatic site, and a sodium level <135 mmol/L. A risk group model was developed that used the number of patient risk factors to predict the risk of TrTD.. In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Databases, Factual; Diarrhea; Drug Administration Schedule; Fatigue; Female; Hand-Foot Syndrome; Humans; Imidazoles; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Models, Statistical; Molecular Targeted Therapy; Mucositis; Niacinamide; Phenylurea Compounds; Predictive Value of Tests; Pyrimidines; Pyrroles; Retrospective Studies; Risk Assessment; Risk Factors; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

To explore the efficacy and safety of pazopanib in a 'real-world' setting in unselected patients, as data regarding unselected patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line pazopanib are limited.. We reviewed records of patients with metastatic ccRCC treated with first-line pazopanib from 1 November 2009 through to 1 November 2012. Cox models were fitted to evaluate the association of progression-free survival (PFS) and overall survival (OS) with patient co-variables.. In all, 88 patients were identified; 74 were evaluable for response: two (3%) had a complete response, 27 (36%) a partial response, 36 (49%) had stable disease and nine (12%) had progressive disease. The median PFS was 13.7 months [95% confidence interval (CI) 8.7-18.3]. PFS was correlated with a Karnofsky Performance Status score of <80 [hazard ratio (HR) 3.26, P < 0.001] and serum lactate dehydrogenase of >1.5 × upper limit of normal (HR 3.25, P = 0.014). The median OS was 29.1 months (95% CI 20.2-not reached). The OS was correlated with brain metastasis (HR 2.55, P = 0.009), neutrophilia (HR 1.179, P = 0.018), and anaemia (HR 3.51, P < 0.001). There were no treatment-related deaths. In all, 53 patients received second-line therapy [vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in 22 patients, mammalian target of rapamycin inhibitors (mTORi) in 22 patients, and other therapy in nine patients]; the median PFS was 8.6 months (95% CI 3.3-25.7) with VEGFR-TKI and 5 months (95% CI 3.5-15.2) with mTORi (P = 0.41); the median OS was 19.9 months (95% CI 12.9-not reached) and 14.2 months (95% CI 8.1-not reached), from initiation of second-line VEGFR-TKI or mTORi, respectively (P = 0.37).. In this retrospective study, first-line pazopanib confirmed its efficacy in metastatic ccRCC. Trends for longer PFS and OS were seen with VEGFR-TKI compared with mTORi after first-line pazopanib.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Drug Therapy, Combination; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sulfonamides; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Brain Edema; Brain Neoplasms; Carcinoma, Renal Cell; Female; Humans; Imidazoles; Indazoles; Lung Neoplasms; Middle Aged; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyrimidines; Radiation Injuries; Sulfonamides

To describe dosing patterns and to compare the drug costs per month spent in progression-free survival (PFS) among patients with advanced renal cell carcinoma (aRCC) treated with everolimus or axitinib following a first tyrosine kinase inhibitor (TKI).. A medical record retrospective review was conducted among medical oncologists and hematologists/oncologists in the US. Patient eligibility criteria included: (1) age ≥18 years; (2) discontinuation of first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons; (3) initiation of axitinib or everolimus as a second targeted therapy during February 2012-January 2013. Real-world dosing patterns were summarized. Dose-specific drug costs (as of October 2014) were based on wholesale acquisition costs from RED BOOK Online. PFS was compared between everolimus and axitinib using a multivariable Cox proportion hazards model. Everolimus and axitinib drug costs per month of PFS were compared using multivariable gamma regression models.. A total of 325 patients received everolimus and 127 patients received axitinib as second targeted therapy. Higher proportions of patients treated with axitinib vs everolimus started on a higher than label-recommended starting dose (14% vs 2%) or experienced dose escalation (11% vs 1%) on second targeted therapy. The PFS did not differ significantly between patients receiving everolimus or axitinib (adjusted hazard ratio (HR) = 1.16; 95% confidence interval [CI] = 0.73-1.82). After baseline characteristics adjustment, axitinib was associated with 17% ($1830) higher drug costs per month of PFS compared to everolimus ($12,467 vs $10,637; p < 0.001).. Retrospective observational study design and only drug acquisition costs considered in drug costs estimates.. Patients with aRCC receiving axitinib as second targeted therapy were more likely to initiate at a higher than label-recommended dose and were more likely to dose escalate than patients receiving everolimus. With similar observed durations of PFS, drug costs were significantly higher-by 17% per month of PFS-with axitinib than with everolimus.

Topics: Aged; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Comorbidity; Disease-Free Survival; Dose-Response Relationship, Drug; Everolimus; Fees, Pharmaceutical; Female; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib

The purpose of the current study was to evaluate the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) who interrupted vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy.. A retrospective analysis of medical records was performed on all patients with mRCC treated with VEGFR-TKIs between January 2008 and July 2014 (n = 505). Patients who achieved stable disease (SD) or a better response under TKI and later discontinued TKI treatment for any reason with the exception of disease progression were included in the analysis.. We identified 32 patients (sunitinib = 20, sorafenib = 7, and pazopanib = 5). The responses to VEGFR-TKIs were complete response (CR, n = 4), partial response (PR, n = 11), SD (n = 15), and controlled but nonmeasurable response (n = 2). Median time to TKI discontinuation from the initiation of VEGFR-TKI therapy was 16.6 months (95 % CI 12.8-20.3), and the main cause of VEGFR-TKI discontinuation was toxicity (n = 19, 59.4 %). At the time of analysis, 16 patients had disease progression and one patient died. With a median follow-up duration of 51.7 months (range 11.5-87.6), median progression-free survival (PFS) after TKI discontinuation was 20.2 months (95 % CI 6.4-34.0). In multivariate analysis, the duration of TKI therapy (<1 year) before TKI discontinuation was an independent significant prognostic factor of poor PFS (p = 0.045). Among 11 patients who were retreated with the same TKI, two patients (18.2 %) achieved PR and nine achieved SD (81.8 %).. VEGFR-TKI could be interrupted at least temporarily when clinically warranted in patients with mRCC sufficiently controlled by TKIs.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Time Factors; Withholding Treatment

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results Included patients (n = 325 for everolimus and n = 127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with <6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup. Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors. Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.

Topics: Aged; Animals; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Everolimus; Female; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome; United States

It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR).. To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR.. A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib.. Relationships with outcomes were analysed using a log-rank test.. A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis.. Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups.. According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

Topics: Aged; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Registries; Response Evaluation Criteria in Solid Tumors; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; Treatment Outcome; Withholding Treatment

Topics: Aged; Brain; Brain Neoplasms; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

To identify the issues of using overall survival (OS) as a primary endpoint in the presence of crossover and the statistical analyses available to adjust for confounded OS due to crossover in oncology clinical trials.. An indirect comparison was conducted between pazopanib and sunitinib in advanced renal cell carcinoma. Statistical adjustment methods were used to estimate the true comparative effectiveness of these treatments. Recently, a head-to-head trial comparing pazopanib and sunitinib was completed. This provided the opportunity to compare the OS treatment effect estimated for pazopanib versus sunitinib using indirect comparison and statistical adjustment techniques with that observed in the head-to-head trial.. Using a rank-preserving structural failure time model to adjust for crossover in the pazopanib registration trial, the indirect comparison of pazopanib versus sunitinib resulted in an OS hazard ratio (HR) of 0.97, while an unadjusted analysis resulted in an OS HR of 1.96. The head-to-head trial reported a final OS HR of 0.92 for pazopanib versus sunitinib.. This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials as Topic; Confounding Factors, Epidemiologic; Cross-Over Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Survival Analysis

Topics: Aged; Antineoplastic Agents; Blister; Carcinoma, Renal Cell; Contrast Media; Drug Eruptions; Hand Dermatoses; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Triiodobenzoic Acids

The present study investigated the various features that might influence the overall survival (OS) of patients with metastatic renal cell carcinoma (RCC) treated with first-line tyrosine kinase inhibitors (TKIs).. A retrospective analysis was performed of consecutive patients with metastatic RCC, in whom treatment with a first-line TKI was initiated from January 2010 to December 2014, at the Department of Oncology, Military Institute of Medicine (Warsaw, Poland). Cox proportional hazards regression was used to construct a prognostic model that included independent factors for OS. We validated the model using 2 bootstrap procedures and calculation of the bias-corrected concordance index.. Of the 266 patients included in the study, 201, 45, and 20 received sunitinib, pazopanib, and sorafenib, respectively. The median OS for the whole cohort was 24.8 months (95% confidence interval, 20.2-29.4 months). Six factors were independently associated with poor survival: Eastern Cooperative Oncology Group performance status > 0 (P < .0001), Fuhrman grade 3 to 4 (P < .0001), hemoglobin less than the lower limit of normal (P < .0001), lactate dehydrogenase greater than the upper limit of normal (P = .0011), neutrophil-to-lymphocyte ratio ≥ 4 (P < .0001), and > 2 metastatic sites (P = .0012). The bias-corrected concordance index was 0.751.. Fuhrman grade and neutrophil-to-lymphocyte ratio are potential factors that affect the survival of patients with metastatic RCC treated with first-line TKIs. The presented prognostic model demonstrated satisfactory performance but requires external validation with a larger data set.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Leukocyte Count; Lymphocyte Count; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; Young Adult

Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect.. Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models.. By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation.. These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683-94. ©2016 AACR.

Topics: A549 Cells; Animals; Carcinoma, Renal Cell; Cell Line; Cell Line, Tumor; Crizotinib; HEK293 Cells; HT29 Cells; Humans; Immunoassay; Indazoles; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Small Molecule Libraries; Stomach Neoplasms; Sulfonamides; Sulfones; Xenograft Model Antitumor Assays

In metastatic ccRCC , the treatment options in 1st line treatment are still the tyrosinkinase inhibitors (TKI) pazopanib and sunitinib, for patients with low or intermediate risk additionally IFNα/bevacizumab and for high risk patients the mTOR inhibitor temsirolimus. In 2nd line following cytokine therapy, axitinib or pazopanib and following TKI /VEGF directed therapy axitinib or everolimus may be administered. New upcoming agents in RCC are the PD1 antibody nivolumab and the multikinase inhibitor Cabozantinib, which both showed an OS advantage compared to everolimus. After marketing authorization in Europe, these agents should therefore be preferred in 2nd and 3rd line therapy. Further agents are under investigation.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

Topics: Aged; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Renal Dialysis; Sulfonamides

Recent data from the COMPARZ study seem to suggest a non-inferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient.. 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT>TT in sunitinib, TT>CC+CT in pazopanib; p<0,0001); VEGF A rs2010963 resulted significant in PFS in sunitinib vs pazopanib patients (GG+CG>CC in sunitinib, CC>GG+CG in pazopanib; p<0,0001); VEGF A rs699947 resulted significant in PFS in sunitinib vs pazopanib patients (AA+AC>CC in sunitinib, CC>AA+AC in pazopanib; p<0,0001). OS showed no statistically significant difference.. in our analysis patients with opposite polymorphisms of rs833061, rs2010963, rs699947 of VEGF A seems to have a better PFS if treated with either sunitinib or pazopanib. Our data seem to suggest that biology could have a role choosing first line treatment for mRCC patients.. a retrospective analysis on 97 histologic samples of mRCC patients was conducted for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs).

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Genotype; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Polymorphism, Single Nucleotide; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Despite existing guidelines for first-line treatment of metastatic renal cell carcinoma (mRCC), prescribing preferences in the United States have not been fully examined. The objectives of this study were to characterize US physicians' preferences and factors influencing first-line mRCC treatment.. A Web-based study presented physicians with hypothetical mRCC patient cases and recorded initial therapy preference and rationale. Descriptive statistics were used to characterize preferred treatment; logistic regression was used to determine patient characteristics associated with therapy changes. Analyses were conducted on pooled responses across cases. Model results were summarized using odds ratios (ORs), 95% confidence intervals, and P values for the covariates.. One hundred nine physicians participated in the study; 96 (88.1%) chose a tyrosine kinase inhibitor as their preferred first-line mRCC treatment (62 [56.9%], sunitinib; 31 [28.4%], pazopanib). Perceived superior overall survival and progression-free survival were top reasons physicians chose sunitinib; enhanced tolerability and efficacy similar to sunitinib were top reasons physicians chose pazopanib. Initial sunitinib prescribers were more likely to change therapy in the presence of comorbid conditions (OR, 2.915; P = .0068), poor Eastern Cooperative Oncology Group performance status (OR, 2.368; P = .0106), or poor prognostic risk (OR, 3.884; P = .0224). This was not seen for initial pazopanib prescribers.. Sunitinib and pazopanib were the most preferred agents for first-line mRCC treatment. Sunitinib preference was driven by perceptions of efficacy, and pazopanib was preferred for its perceived tolerability and efficacy similar to sunitinib. With varying clinical scenarios, initial pazopanib prescribers were more likely to maintain pazopanib and alter dosing; sunitinib prescribers were more likely to switch therapy.

Topics: Aged; Carcinoma, Renal Cell; Drug Prescriptions; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Practice Guidelines as Topic; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; United States

For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS).. Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008-2010 Cohort (n = 645) and a 2011-2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies.. Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008-2010 Cohort; 35 % in the 2011-2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84-0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005).. Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Prescriptions; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Logistic Models; Male; Middle Aged; Molecular Targeted Therapy; Netherlands; Pyrimidines; Pyrroles; Registries; Retrospective Studies; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; Young Adult

With the exception of temsirolimus, clinical trials in metastatic renal cell carcinoma (mRCC) with poor-risk features are lacking. We previously showed that vascular endothelial growth factor receptor tyrosine kinase inhibitors are active and well tolerated by poor-risk group. This study evaluated and compared the efficacy and safety of pazopanib and sunitinib in this group.. We reviewed the medical records of all patients with mRCC who had received pazopanib or sunitinib at Asan Medical Center. We only assessed patients who had three or more poor-risk features as determined in the advanced renal cell carcinoma trial.. Between December 2006 and April 2015, a total of 172 patients who met the inclusion criteria received pazopanib (n = 72) or sunitinib (n = 100). The clinical characteristics were as follows in the pazopanib/sunitinib groups: median age = 60/57 years (range 34-80/17-83); clear cell type = 65/80 (90/80 %); and prior nephrectomy = 46/56 (64/56 %). The disease control rates in the pazopanib/sunitinib groups were 82/60 % (p = 0.002). With a median follow-up duration of 14.2 months (range 1.6-65.0), the median overall survival and progression-free survival in the pazopanib/sunitinib groups were 14.4/8.9 (p = 0.030) and 9.8/4.3 months (p = 0.040), respectively. The common all-grade toxicities for pazopanib/sunitinib were anemia (32 vs. 77 %), neutropenia (33 vs. 56 %), increased aspartate aminotransferase or alanine aminotransferase levels (36 vs. 35 %), fatigue (38 vs. 55 %), and hand-foot syndrome (17 vs. 51 %).. Pazopanib and sunitinib are both active and well tolerated in mRCC patients with poor-risk features, but pazopanib might be more effective in this group.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Pyrroles; Retrospective Studies; Risk Factors; Sulfonamides; Sunitinib; Survival Rate; Treatment Outcome; Young Adult

To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients.. A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists.. In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib.. Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.

Topics: Aged; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Cohort Studies; Computer Communication Networks; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Sunitinib and pazopanib are among the most prescribed targeted therapies for the systemic management of advanced renal cell carcinoma (RCC), but published cost comparisons between the 2 agents are few and limited by methodological and population differences. Also, sunitinib is administered on a 4-week on/2-week off cycle, and pazopanib is taken continuously. Thus, appropriate use and cost comparisons between the 2 drugs require methodological approaches to account for these differences. One way to accomplish this is to substitute expected for observed days supply. Recognizing the effects of nonrepresentative days supply values is important for assessing real-world treatment patterns and costs.. To (a) characterize demographic and clinical characteristics among patients with RCC newly initiating sunitinib or pazopanib, using a large administrative claims dataset; (b) characterize treatment patterns, persistence, and costs for each treatment group; and (c) assess the effect on treatment patterns and costs for sunitinib by substituting 42 days for prescriptions with 28- or 30-day supplies to account for sunitinib's 4-week on/2-week off dosing schedule.. This was a retrospective cohort study using health care claims data from the Truven MarketScan Research Databases, which include enrollment information and medical and pharmacy claims. Baseline patient demographic and clinical characteristics and treatment patterns (continuation, discontinuation, switching, or interruption; days supply; and persistence) were compared. Health care costs were calculated as mean daily index medication costs and as total, medical, and medication (all-cause and RCC-related) costs over the 12 months post-index period. Inclusion criteria were continuous health plan enrollment between 6 months pre-index and 12 months post-index; no RCC medications 6 months pre-index; ≥ 2 RCC diagnoses within ±180 days of index; and age ≥ 20 years. For demographic and clinical characteristics, treatment patterns, and costs, means (± standard deviations) for continuous data and relative frequencies for categorical data were reported. Chi-square tests or Student t-tests were used to evaluate differences other than costs. A generalized linear model with gamma distribution and log link was used for evaluating costs, controlling for patient demographic and pre-index clinical characteristics, persistence days, and index medication. All statistical tests were 2-tailed with significance set at P < 0.05 for all comparisons except for interactions with significance set at P < 0.10. The effects of substituting 42 days supply for sunitinib prescription records with 28 or 30 days supply were determined.. In total, 609 (15.1% of the sunitinib overall sample) sunitinib patients and 183 (8.3% of the pazopanib overall sample) pazopanib patients were included. Demographic and clinical characteristics were similar for each treatment cohort. The persistence periods and number of prescriptions filled were also similar. Without substitution, significant differences were observed between treatment groups in patterns of index medication use (overall P = 0.0409), with fewer patients taking sunitinib continuing treatment than patients taking pazopanib. However, with substitution, treatment patterns differed significantly (overall P = 0.0026), but with more sunitinib patients than pazopanib patients continuing treatment. Without substitution, unadjusted daily mean index medication costs were significantly different for sunitinib ($216) versus pazopanib ($177, P < 0.0001). Substitution of sunitinib days supply eliminated the significant differences in daily index medication costs between treatment groups. The 1-year RCC-related and all-cause medication, medical, and total unadjusted costs were not significantly different between treatment groups, and substitution had no effect on these costs. After adjustment for possible confounding factors, these cost results were similar to those found with unadjusted analyses.. In this study, patients with RCC who were initiating sunitinib and pazopanib had similar demographic and clinical characteristics and drug persistence patterns. The effect of substituting days supply values was demonstrated as an approach to considering differences in dosing cycles. Substitution significantly reduced sunitinib mean daily index medication costs and eliminated or reversed the direction of significant differences in costs between drugs during the persistence period. No significant differences were observed in unadjusted or adjusted 1-year costs.. This study was funded and conducted fully by Pfizer. All authors are employees of Pfizer. This work was presented in part as posters at the 2015 Genitourinary Cancers Symposium, of the American Society of Clinical Oncology; Rosen Shingle Creek, Orlando, FL; February 26-28, 2015, and the 20th Annual International Meeting of the International Society for Pharmacoeconomics and Outcomes Research; Philadelphia, PA; May 16-20, 2015. All authors contributed to study concept and design and to data interpretation. Mardekian was primarily responsible for data collection, along with Harnett. MacLean and Harnett worked on the manuscript, which was revised by MacLean and Mardekian.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cohort Studies; Female; Health Care Costs; Humans; Indazoles; Indoles; Male; Middle Aged; Prescription Fees; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; Young Adult

To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies.. This retrospective study included 146 patients with mRCC who were treated during 2007-2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (≤3 monthsnths, 3-18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1-3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models.. The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease-free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05).. We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

The efficacy and/or tolerability of pazopanib in patients with metastatic renal cell carcinoma (mRCC) have been found to differ in Western and Asian populations. This retrospective multicenter study analyzed the results of first-line pazopanib treatment in 93 consecutive patients with mRCC who were treated at the medical oncology departments of three tertiary cancer centers in Seoul, Korea.. The decision to administer pazopanib as first-line therapy was at the discretion of the treating physician in all patients with mRCC. Patients enrolled in clinical trials were excluded to ensure that the results would reflect real-world outcomes representative of daily clinical settings. All patients received 800 mg/day pazopanib. Outcomes included response rate, progression-free survival (PFS), overall survival (OS), and safety.. The 93 patients included72 (77 %) male and 21 (23 %) female individuals, of median age 65 years (range, 19-84 years). The median number of metastatic sites per patient was two (range, 1-5), with the lungs being the most frequently involved site. Most patients had favorable (n = 46) or intermediate (n = 36) risk as determined by Memorial Sloan Kettering Cancer Center criteria. Pazopanib was generally welltolerated: the major hematologic adverse effect was grade 1/2 anemia (14 %); and the most frequently observed non-hematologic toxicity was grade 1/2 mucositis (22 %), followed by hair discoloration and hypertension. Of the 93 patients, three (3 %) showed complete response, 52 (56 %) showed partial response, and 21 (23 %) showed stable disease, making the objective response rate 59 % and the disease control rate 82 %. At a median follow-up of 21 months, the estimated median PFS and OS were 12.2 months (95 % confidence interval, 7.1-17.4 months) and 21.9 months (95 % confidence interval, 12.9-30.9 months), respectively.. In this retrospective study, first-line therapy with pazopanib demonstrated clinically relevant efficacy and tolerability in unselected real-world Korean patients with mRCC. OS and PFS of these Korean patients were similar to those reported in phase III trials.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Republic of Korea; Retrospective Studies; Sulfonamides; Young Adult

Sunitinib (SU) and pazopanib (PZ) are standards of care for first-line treatment of metastatic renal cell carcinoma (mRCC). However, how the efficacy of these drugs translates into effectiveness on a population-based level is unknown.. We used the International mRCC Database Consortium (IMDC) to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS (OS2) and second-line PFS (PFS2) were also evaluated.. We obtained data from 7438 patients with mRCC treated with either first-line SU (n = 6519) or PZ (n = 919) with an overall median follow-up of 40.4 months (95% confidence interval [CI] 39.2-42.1). There were no significant differences in IMDC prognostic groups (p = 0.36). There was no OS difference between SU and PZ (22.3 versus 22.6 months, respectively, p = 0.65). When adjusted for IMDC criteria, the hazard ratio (HR) of death for PZ versus SU was 1.03 (95% CI 0.92-1.17, p = 0.58). There was no PFS difference between SU and PZ (8.4 versus 8.3 months, respectively, p = 0.17). When adjusted for IMDC criteria, the HR for PFS for PZ versus SU was 1.08 (95% CI 0.981-1.19, p = 0.12). There was no difference in RR between SU and PZ (30% versus 28%, respectively, p = 0.15). We also found no difference in any second-line treatment between either post-SU or post-PZ groups for OS2 (13.1 versus 11 months, p = 0.27) and PFS2 (3.7 versus 5.0 months, p = 0.07).. We confirmed in real-world practice that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Indoles; Kidney Neoplasms; Middle Aged; Molecular Targeted Therapy; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib

Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cholesterol; Ferritins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Hypothyroidism; Indazoles; Indoles; Iron; Kidney Neoplasms; Lipids; Metabolome; Models, Theoretical; Neoplasm Metastasis; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Triglycerides

Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) are widely used for the treatment of metastatic renal cell carcinoma (mRCC). The aim of this study was to investigate the association between treatment-related hypertension and the therapeutic efficacy of VEGFR-TKIs.. Clinical data of 155 mRCC patients treated with VEGFR-TKIs at the Cancer Hospital of Chinese Academy of Medical Sciences from 2006 to 2014 were retrospectively analyzed. All patients received first-line TKI therapy. Among them, 69 patients were treated with sunitinib, 14 cases with pazopanib, and 51 cases with fazotinib. Kaplan-Meier curves were used to evaluate the survival of the patients.. The median survival for the whole group (n=155) was 36.2 months. Among the 98 (63.2%) patients who developed hypertension, 9 patients (5.8%) were evaluated as grade Ⅰ, 54 (34.8%) as grade Ⅱ and 35 (22.6%) as grade Ⅲ, and there was no patient with grade Ⅳ hypertension. The occurrence of TKI-related hypertension was correlated with age and MSKCC score (P<0.05), while not significantly correlated with gender, nephrectomy, T stage, number of metastases, lung metastasis or sunitinib treatment (P>0.05 for all). For the whole group (n=155), the therapeutic efficacy rate was 43.2% (67/155), the median progression-free survival (PFS) was 12.0 months, and the median overall survival (OS) was 36.2 months. The response rate (RR) was 26.3% (15/57) in patients with normal blood pressure and 53.1% (52/98) in patients with hypertension (P=0.001). The median PFS was 7.1 months in the cases with normal blood pressure and 13.8 months in patients with hypertension (P=0.032). The response rates were 33.3% (3/9), 51.9% (28/54) and 60.0% (21/35) in patients with grade Ⅰ, Ⅱ and Ⅲ hypertension (P=0.006). The median PFS was 7.1, 9.7, and 12.0 and 19.5 months in patients with normal blood pressure, and patients with grade Ⅰ, Ⅱ and Ⅲ hypertension, respectively (P=0.039). Both univariant and multivariant analyses indicated that treatment-related hypertension is an important predictive factor for the efficacy of VEGFR-TKIs therapy.. Hypertension might be an effective predictive factor for efficacy of VEGFR-TKIs therapy in mRCC patients. Large-sample studies are warranted to further prove these results.

Topics: Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Hypertension; Indazoles; Indoles; Kidney Neoplasms; Male; Neoplasm Metastasis; Nephrectomy; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Intra-tumour heterogeneity is a common molecular phenomenon in metastatic clear cell renal carcinoma (mRCC), representing the genetic complexity of a tumour with multiple metastatic sites. The present commentary discusses the observed phenomena of phenotypic intra-tumour heterogeneity in mRCC patients treated with the tyrosine kinase inhibitors sunitinib or pazopanib. Here, drug response can be different on the level of each evaluated metastasis in the individual patient. This questions the currently used radiologic staging systems of RECIST criteria and demands for a modification of radiologic response assessment with the consequence of a patient-tailored therapy in the clinical setting.Please see related article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0729-9 .

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Genetic Heterogeneity; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Pharmacogenomic Testing; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Response Evaluation Criteria in Solid Tumors; Sulfonamides; Sunitinib

Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma.. Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy.. A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival.. Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib

Renal cell cancer has been rarely reported as a cause of gastric or esophageal metastases. They usually present with gastrointestinal bleeding and most cases have been managed surgically or endoscopically. We report the case of a 38-year-old man with a 4-year history of metastatic renal cell carcinoma admitted to the emergency room with melena and anemia. At endoscopy, three esophageal polypoid lesions (middle and distal thirds) and a 7 cm mass in the gastric fundus were identified. Biopsy revealed esophageal mucosa infiltrated by renal cell carcinoma. Radiotherapy was administered (30 Gy in 10 fractions), followed by pazopanib, with excellent tolerance and without new bleeding episodes. Computed tomography scan showed complete disappearance of the esophageal and fundic lesions at 3 months follow-up. Twenty-four months after being initiated on pazopanib, there is no radiological evidence of disease. This is the first reported case showing complete remission of gastric and esophageal metastases after treatment with radiotherapy and pazopanib.

Topics: Adult; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Esophageal Neoplasms; Gastric Fundus; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Stomach Neoplasms; Sulfonamides

Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood.. Study eligibility was limited to patients with 2 prior lines of therapy, including at least 1 vascular endothelial growth factor directed therapy, as well as ECOG performance status 0 to 2 and clear cell histology. Patients received pazopanib 800 mg daily. A Simon minmax 2-stage design was used with 80% power to determine an encouraging 23% overall response rate (10% type I error). Immunological profiles were assessed monthly on a Luminex® platform using the Human Cytokine 30-Plex Cytokine Immunoassay (Invitrogen™).. A total of 28 patients with a median age of 63 years (range 45 to 86) were enrolled in study. Of the patients 12 (43%) had a confirmed complete (1) or partial (11) response. In the cohort median progression-free survival was 16.5 months (95% CI 14.7-not reached). The most common grade 3/4 toxicities were hypertension (46% of cases) and proteinuria (14%). At 6 and 12 months responders had lower levels of HGF, VEGF, IL-6 and 8, and soluble IL-2R (each p <0.05). Nonresponders also showed increased numbers of myeloid-derived suppressor cells at each interval. Phenotypic and functional studies confirmed that the myeloid-derived suppressor cells were granulocytic.. Progression-free survival and the overall response rate associated with third line pazopanib were encouraging. Immunological profile differences between responders and nonresponders suggest that the mechanism of pazopanib resistance is at least partly related to the generation of systemic tumor immune tolerance.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Time Factors; Treatment Outcome

VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.. We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.. rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10(-37)). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01).. Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.

Topics: Adolescent; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Genome-Wide Association Study; Humans; Indazoles; Kidney Neoplasms; Male; Polymorphism, Single Nucleotide; Pyrimidines; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Young Adult

Several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a tumor flare (TF) but its clinical relevance is still questionable.. This analysis investigates the occurrence of tumor flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC.. Patients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2.. Overall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 - GR1). Cox proportional hazards regression was used to assess the prognostic role.. Sixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] -0.07 to 0.53) and 0.70cm/mo (IQR 0.21-1.46), respectively (p=0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08-1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001-1.225; p=0.048).. This study reports clinical evidence that TKI discontinuation results in acceleration of tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients.. In this report, we looked at the outcomes for patients affected by metastatic kidney tumors who discontinued treatment with antiangiogenic agents. We found that tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in tumor growth rate, which is related to patient survival.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Proportional Hazards Models; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Withholding Treatment

Clinical trials have demonstrated that pazopanib prolongs progression-free survival (PFS), with an acceptable safety profile, for patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mammalian target of rapamycin (mTOR) inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. The present study evaluated the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting.. The present study was a retrospective analysis of eligible patients in US Oncology's iKnowMed electronic health records database who had been treated for aRCC from November 1, 2009 to August 31, 2012. The patients received first-line therapy with pazopanib (cohort 1), followed by second-line therapy with either everolimus or temsirolimus (cohort 2). The key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use.. The median OS in cohort 1 (n = 177) was 22 months, and the median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). The median persistence was 151 days with pazopanib. The median OS in cohort 2 (n = 35) was 16 months; the median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). The median persistence was 93 days with everolimus and 49 days with temsirolimus.. The outcomes for the patients treated with first-line pazopanib in the community setting were consistent with those reported by previous prospective and retrospective studies. Although the second-line cohort was small, the results of mTOR inhibitors after pazopanib were also consistent with those of previous observations.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Community Networks; Electronic Health Records; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Longitudinal Studies; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; United States; Young Adult

Pazopanib was noninferior to sunitinib in progression-free survival in a phase III, open-label, randomized clinical trial comparing the efficacy and safety of the 2 drugs for treatment of patients with advanced renal cell carcinoma (RCC). A secondary analysis of this trial conducted on patient-reported health care resource utilization (HCRU) endpoints revealed significantly fewer monthly telephone consultations and emergency department visits among patients treated with pazopanib over the first 6 months of treatment.. To (a) compare total costs of HCRU and adverse events (AEs) in patients with advanced RCC receiving first-line pazopanib or sunitinib from the phase III clinical trial and (b) perform a post hoc economic analysis that applied direct medical care and pharmacy unit costs, obtained from the Truven Health MarketScan Databases, to HCRU and AE rates.. Total HCRU costs included components for provider contacts, diagnostics, hospitalizations, procedures, and study/nonstudy drugs. Patients were stratified by the presence or absence of an AE in order to estimate costs attributable to AEs. Costs were adjusted to 2013 U.S. dollars. The highest 1% of cost outliers were equally excluded from each group. Univariate (t-test and Kaplan-Meier sample average [KMSA]) and multivariate (using treatment group and region as covariates) analyses were performed.. A total of 906 patients (pazopanib, n = 454; sunitinib, n = 452) reported HCRU; higher rates were observed for sunitinib. In unadjusted cost analyses, the mean total costs for pazopanib-treated patients were 8.0% lower than those treated with sunitinib ($80,464 vs. $86,886; P = 0.20). The difference in KMSA-estimated costs was significantly higher for sunitinib versus pazopanib ($156,128 vs. $143,585; P = 0.003). Adjusted cost differences between arms consistently suggested higher costs for sunitinib. Among patients who experienced greater than or equal to 1 AE, costs were $8,118 higher for pazopanib-treated patients and $14,343 for sunitinib-treated patients.. The findings suggest that health care costs were lower among patients with advanced RCC treated first-line with pazopanib versus sunitinib.

Topics: Carcinoma, Renal Cell; Female; Health Care Costs; Health Services; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; United States

Current first-line treatments for metastatic renal cell carcinoma (mRCC) include the multityrosine kinase inhibitors pazopanib and sunitinib. Both agents had similar progression-free survival (PFS) and overall survival (OS) in the COMPARZ trial (Comparing the Efficacy, Safety and Tolerability of Pazopanib versus Sunitinib); however, the adverse event profiles of the 2 agents are different. In the PISCES trial (Patient Preference Study of Pazopanib versus Sunitinib in Advanced or Metastatic Kidney Cancer), patients and physicians preferred pazopanib primarily because it offered better health-related quality of life (HRQoL) and caused less fatigue.. To compare the cost-effectiveness of pazopanib versus sunitinib from a U.S. health care system perspective in the first-line treatment of patients with mRCC.. A partitioned-survival analysis model with 3 health states (preprogression, postprogression, and dead), data from 2 randomized controlled trials of pazopanib versus sunitinib (COMPARZ and PISCES), and secondary sources were used to calculate the incremental cost per quality-adjusted life-year (QALY) gained for pazopanib versus sunitinib. A time horizon of 37.5 months was used in the base case, consistent with the duration of follow-up used in the COMPARZ trial. The proportion of patients in each health state over time was based on Kaplan-Meier survival distributions for PFS and OS from the COMPARZ trial. Utility values were obtained from the PISCES trial. Costs were based on medical resource utilization data from the COMPARZ trial and unit costs from secondary sources. Probabilistic sensitivity analyses and deterministic sensitivity analyses were conducted.. In the base case, pazopanib was estimated to provide more QALYs at a lower cost compared with sunitinib (pazopanib dominant). In probabilistic sensitivity analyses, pazopanib was projected to be dominant in 69% of the simulations. The probability that pazopanib was more cost-effective than sunitinib was ≥ 90% for threshold values of cost-effectiveness between the range of $10,000-$160,000 per QALY gained. In deterministic sensitivity analyses, pazopanib was dominant in all scenarios examined.. Results of this study suggest that pazopanib is cost-effective compared with sunitinib as the first-line treatment of patients with mRCC in the United States.

Topics: Carcinoma, Renal Cell; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Models, Economic; Pyrimidines; Pyrroles; Quality of Life; Quality-Adjusted Life Years; Sulfonamides; Sunitinib; Survival Analysis; United States

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma.

Topics: Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).. The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).. In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.. Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Indoles; Interleukin-8; Kidney Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sulfonamides; Sunitinib; Survival Analysis; Young Adult

Renal cell carcinoma (RCC), normally considered an intrinsically chemotherapy-resistant cancer, is currently treated with targeted biologic therapies, including antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib. The efficacy of these agents is limited by both intrinsic and acquired resistance. Death is almost always due to advanced metastatic disease, a treatment circumstance seldom modeled in preclinical (mouse) drug testing. Similarly, therapy results using postsurgical adjuvant therapy models of microscopic disease have not been reported. Using in vivo selection and transfection of established human RCC cell lines (786-0 and SN12-PM6), we derived clonal luciferase-expressing variants capable of spontaneous metastasis from an orthotopic primary tumor to organs typical of clinical RCC, including bone, lungs, and brain. The bioluminescence and consistent metastatic spread of von Hippel-Lindau-wild type SN12-PM6-1 cells allowed for the establishment of perioperative therapy models of RCC. We report that the combination of daily low-dose metronomic topotecan with pazopanib has highly potent antiprimary tumor as well as both postsurgical adjuvant and metastatic therapy efficacy despite lack of an antimetastatic effect of pazopanib monotherapy. The combination therapy resulted in sustained metastatic tumor cell dormancy, but tumor progression occurred upon treatment cessation. We also obtained evidence for a direct effect of pazopanib on RCC cells, resulting in increased intracellular concentration of topotecan. Our results suggest that this type of treatment combination should be considered for clinical evaluation in early- or late-stage metastatic disease, even for tumors seemingly intrinsically "resistant" to antiangiogenic TKIs or chemotherapy.

Topics: Administration, Metronomic; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Drug Synergism; Humans; Indazoles; Kidney Neoplasms; Maximum Tolerated Dose; Neoplasm Metastasis; Pyrimidines; Sulfonamides; Survival Analysis; Topotecan; Xenograft Model Antitumor Assays

Topics: Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Biopsy; Carcinoma, Renal Cell; Fatal Outcome; Humans; Immunohistochemistry; Indazoles; Kidney Neoplasms; Male; Neoplasm Recurrence, Local; Nose Neoplasms; Pyrimidines; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome

For first-line therapy options for advanced renal cell carcinoma (RCC), clinical trials have demonstrated similar efficacy for pazopanib and sunitinib as well as differing side-effect profiles, which may affect patient persistence in self-administration of these oral medications. However, the treatment patterns of each drug in real-world clinical practice, as opposed to the controlled environment of a trial, have not been directly compared.. To compare persistence and compliance (adherence) with pazopanib versus sunitinib in a real-world setting.. This was a retrospective claims analysis using 2 databases: Optum Research Database and Impact National Benchmark Database. Eligible patients included adult patients (aged ≥ 18 years) with ≥ 2 RCC diagnoses and evidence of first-line therapy with ≥ 1 subsequent pharmacy claim for pazopanib or sunitinib between October 2009 and July 2012. The date of the first pazopanib or sunitinib claim was defined as the index date. Additional requirements included continuous enrollment in the health plan for 2 months prior (baseline period) through 6 months after (follow-up period) the index date and no cancers other than those associated with RCC. Propensity score matching was used to minimize selection bias. Persistence with the index drug was compared using days to discontinuation, estimated level of persistence (ELPT) at 180 days, and proportion of days covered (PDC). PDC was defined by dividing the number of days covered with the index drug by the number of follow-up days. Compliance was estimated using medication possession ratio (MPR). For matched cohort pairs with > 1 fill, MPR was defined by dividing the number of days covered with the index drug by the number of days between the first and last index medication fill.. We identified 84 matched pairs among 97 patients prescribed pazopanib and 349 prescribed sunitinib. Among the matched population, mean comorbidity index score was 5.8 (95% CI = 1.8-6.0) for pazopanib, and 6.1 (95% CI =1.8-6.0) for sunitinib (P = 0.133). Evidence of any radiation therapy during the baseline period was significantly higher among the sunitinib cohort prior to matching (9% vs. 18%, P = 0.043), and evidence of surgery was higher in the pazopanib cohort after matching (12% vs. 7%, P = 0.046). Cohorts were balanced according to demographic and clinical characteristics with mean (SD) age of 63.0 (9.0) years and 77.4% male. During the 6-month period after drug initiation, there was no significant difference (P > 0.05) by drug cohort in the duration of index drug therapy or the percentage of patients who discontinued their index drugs. The mean (SD) time to discontinuation was 133.4 (62.8) days and 139.9 (55.6) days among the matched pazopanib and sunitinib cohorts, respectively (P = 0.445). In both cohorts, more than 40% of patients discontinued their index drugs (46.4% pazopanib and 44.1% sunitinib, P = 0.732). In addition, there was no significant difference by drug cohort in the ELPT at any time examined between 30 and 180 days after initiation of therapy. PDC with the index drug during the fixed 6-month follow-up was also examined. Although the mean PDC was significantly higher among the sunitinib cohort (0.77 vs. 0.68 for pazopanib, P = 0.037), there was no difference by cohort in the percentage of patients with high PDC (defined as ≥ 80%): 52.4% versus 56.0% for pazopanib and sunitinib, respectively (P = 0.622). Mean MPR among matched pairs with at least 2 fills for the index drug was significantly higher among the sunitinib cohort, although there was no difference by cohort in the percentage of patients with high MPR (defined as ≥ 80%): 81.4% versus 93.2% for pazopanib and sunitinib, respectively (P > 0.071).. In the first 6 months of treatment, persistence and compliance to pazopanib and sunitinib were similar. Future studies are needed, including those assessing larger cohorts and longer follow-up periods.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Databases, Factual; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Medication Adherence; Middle Aged; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; United States

We report a case of an 82-year-old man with renal cell carcinoma who developed a cardiac metastasis within the interventricular septum. He had been under watchful waiting for indolent metastatic renal cell carcinoma for many years before developing symptoms consistent with heart failure. At this time, a 44 mm interventricular septal mass, consistent with a cardiac metastasis, was identified as the cause of his symptoms. Pazopanib was initiated which led to both a clinical and radiological response.

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Heart Neoplasms; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Pyrimidines; Sulfonamides; Watchful Waiting

Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin-2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered therapeutics in RCC patients has been implicated in impairing T cell activation and proliferation in vitro. In this work, we addressed whether this notion holds true for expansion of tumor-infiltrating lymphocytes (TILs) in sunitinib-treated patients. We compared resected primary RCC tumor material of patients pretreated with sunitinib with resection specimen from sunitinib-naïve patients. We found improved TIL expansion from sunitinib-pretreated tumor digests. These TIL products contained more PD-1 expressing TIL, while the regulatory T cell infiltration was not altered. The improved TIL expansion was associated with reduced intratumoral myeloid-derived suppressor cell (MDSC) content. Depletion of MDSCs from sunitinib-naïve RCC tissue-digest improved TIL expansion, proving the functional relevance of the MDSC alteration by sunitinib. Our in vivo results do not support previous in vitro observations of sunitinib inhibiting T cell function, but do provide a possible rationale for the combination of sunitinib with immunotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Everolimus; Female; Humans; Immunotherapy; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Molecular Targeted Therapy; Myeloid Cells; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib; T-Lymphocytes; Treatment Outcome

Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC), but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL) gene status, vascular endothelial growth factor receptor (VEGFR) or stem cell factor receptor (KIT) expression, and their relationships with characteristics and clinical outcome of advanced ccRCC.. A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS) and overall survival (OS) were calculated and then compared based on expression status. The Chi-square test, the Kaplan-Meier method, and the Lon-rank test were used for statistical analyses.. Of 59 patients, objective responses were observed in 28 patients (47.5%). The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6%) had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%). VHL mutation status did not correlate with either overall response rate (P = 0.938) or PFS (P = 0.277). The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043).. VHL mutation status could not predict the efficacy of sunitinib or pazopanib. Further investigation of VHL/VEGFR pathway components is needed.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Immunohistochemistry; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Prognosis; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein; Young Adult

In many European jurisdictions, relative effectiveness assessments (REAs) of pharmaceuticals are performed during the reimbursement decision-making process. International collaboration in the production of these assessments may prevent the duplication of information in various jurisdictions. A first pilot of a joint REA (pazopanib for the treatment of renal cell carcinoma) was published in 2011.. The objective was to investigate how well the methods used in the joint REA match the methods used in the national/local assessments on the same topic.. National/local assessments from European jurisdictions, available in English language, were identified through a literature search and an e-mail request to health technology assessment organizations. Data were abstracted from joint and national/local assessments using a structured data abstraction form. Results were compared for differences and similarities.. In total, five national/local reports were included (Belgium, England/Wales, France, The Netherlands, and Scotland). The general methods (indication, main comparator, main end points, main trial) were similar. The details of the assessment (e.g., exact wording of indication, additional comparators, additional trials included, and method of indirect comparison), however, varied. Despite these differences, the joint REA included nearly all comparators, end points, trials, and methods of analysis that were used in national/local REA reports.. This study has shown overlap in the methods national/local REA bodies in Europe have chosen for a pazopanib REA for renal cell carcinoma, except for the use and methods of indirect comparisons. Although some additional comparators and outcomes differed between national/local REAs, they can be captured in a comprehensive joint REA.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Comparative Effectiveness Research; Cooperative Behavior; Cost-Benefit Analysis; Decision Support Techniques; Drug Costs; Europe; Humans; Indazoles; Insurance, Health, Reimbursement; International Cooperation; Kidney Neoplasms; Models, Economic; Prohibitins; Pyrimidines; Sulfonamides; Treatment Outcome

Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials.. In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices.. A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received.. Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Patients; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

The objective of this study was to compare treatment characteristics, survival and costs for sunitinib and pazopanib for advanced renal cell carcinoma (RCC) in a real-world setting.. Using claims data, this observational, retrospective cohort study selected individuals aged 19 to 89 years, with commercial or Medicare insurance, advanced RCC, and at least one pharmacy claim for sunitinib or pazopanib between 1 November 2009 and 31 December 2012. Treatment characteristics (treatment interruption, adherence, duration and discontinuation), survival, and costs were measured up to 12 months. Statistical models were adjusted for age, gender, geographic region, race, and RxRisk-V score.. At baseline, pazopanib patients exhibited significantly worse health status indicators (RxRisk-V score, number of pharmacy claims, and pre-index total healthcare costs) than sunitinib patients. There were no differences in treatment characteristics or survival. Index medication costs (mean difference $5580, p = 0.03, adj p = 0.05) and total healthcare costs (mean difference $12,192, p = 0.09, adj p = 0.07) trended higher with sunitinib. Patients non-adherent with sunitinib incurred significantly higher total costs compared to patients non-adherent with pazopanib (mean difference $17,680, p = 0.04, adj p = 0.01).. Mortality data and proxy variables for treatment effectiveness indicate comparable clinical value for both medications. Sunitinib treatment trended towards higher index medication and total healthcare costs despite higher pre-index total costs and worse health status indicators at baseline with pazopanib. Non-adherence with sunitinib was associated with significantly higher total healthcare costs, which may indicate differences in tolerability between the two agents and requires further investigation.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Cohort Studies; Drug Costs; Female; Health Care Costs; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Medicare; Middle Aged; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Retrospective Studies; Sulfonamides; Sunitinib; Treatment Outcome; United States; Young Adult

The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy of metastatic renal cell carcinoma (mRCC).. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Association for Urology (2013), the European Society of Medical Oncology (2012), the National Institute of Health and Clinical Excellence (2011), the Canadian Kidney Cancer Forum (2013) and the Asian Oncology Summit (2012). Recommendations on the first-, second- and third-line treatment for mRCC were developed.. These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of mRCC.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Singapore; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

There were observed 30 patients (32 tumors), to whom preoperatively for renal-cell cancer (ROC) a neoadjuvant target therapy (NATTH) was conducted. In 19 (66.7%) of them a pazopanib (800 mg per os once a day through 2 mo) was applied, and in 10 (33.3%)--sunitinib (50 mg per os once a day through 28 days, the gap--14 days, repeated course--28 days). The indications for the NATTH conduction were: in 7 (21.9%) patients--a locally--spread RCC with the objective to localize a tumor and to search a further possibility of radical surgical intervention performance, and in 25 (78.1%)--the tumor reduction and searching possibility of the organpreserving treatment conduction. The NATTH conduction in the patients, suffering RCC, have guaranteed a primary pathological focus reduction in 90% of observations, and a partial regression in accordance to the RECIST criteria--in 28.1%. A tumor reduction by (22.9 ± 17.8)% at average have permitted to perform a renal resection in 75% of observations, concerning localized RCC, when indication of preservation of enough functioning renal parenchyma was secured.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Indazoles; Indoles; Kidney; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Nephrectomy; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden

There are no robust data on hemoglobin (Hb), lactate dehydrogenase (LDH), and calcium variability for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. We aim to evaluate prognostic implications of Hb, LDH, and calcium variability and establish a novel risk stratification model in RCC patients receiving targeted therapies.. We retrospectively studied an unselected cohort of patients with mRCC, who were treated with tyrosine kinase inhibitors. We assessed LDH variability, Ca variability, and Hb variability with various methods using standard deviation and fluctuation across thresholds. Kaplan-Meier and log-rank analyses were employed on OS and multivariate Cox proportional hazard model analyzed clinical parameters for their prognostic relevance.. A total of 59 patients intermediate-risk group according to the Memorial Sloan-Kettering Cancer Center with mRCC who had early progressed after first-line therapy with interferon-α were included in this retrospective single-center study conducted between February 2008 and December 2011. The mean Hb was 12.4 g/dl (min-max 9.1-15.2) throughout the study. Multivariable-adjusted Cox regression showed that patients in the consistently low-Hb group and patients in the low-amplitude and high-amplitude groups had a statistically significant increase in risk compared with patients who were consistently on target (HR 4.1; 95 % CI 1.3-12.9 and HR 2.9; 95 % CI 1.05-8.1 and HR 4.4; 95 % CI 1.7-11.1, respectively). On the other hand, the higher mean LDH (LDH more than 1 >upper limit of normal) was associated with OS. LDH variability and Ca variability were not associated with mortality.. In patients with mRCC treated with VEGF-targeted therapy, Hb variability and mean LDH level might be associated with OS. This should be investigated prospectively.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Calcium; Carcinoma, Renal Cell; Disease-Free Survival; Female; Hemoglobin A; Humans; Indazoles; Indoles; Kidney Neoplasms; L-Lactate Dehydrogenase; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Risk Assessment; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; Vascular Endothelial Growth Factor A

Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown.. mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3).. Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001).. The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Eligibility Determination; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Karnofsky Performance Status; Kidney Neoplasms; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

In a phase III trial for patients with metastatic renal cell carcinoma, pazopanib and sunitinib offered comparable progression-free survival, but pazopanib scored higher on quality-of-life indices.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Sunitinib

Chemotherapy for collecting duct carcinoma (CDC) has demonstrated only limited efficacy in the advanced setting. The present study evaluated the activity of targeted therapies in metastatic CDC.. We evaluated a cohort of 384 consecutive patients with metastatic renal cell carcinoma (mRCC). The characteristics of patients with CDC were compared against those of the remaining cohort. All patients with CDC were treated with targeted therapies.. Thirteen patients with advanced CDC were referred to our Center (incidence: 3.4% of all mRCC). Median age was 57 and 62 years in the CDC and non-CDC groups, respectively. The overall disease control in the CDC population was 23%, and median overall survival was 4 (95% confidence interval(CI)=2.4-5.6) months. Three patients obtained a satisfying response (disease control lasting 6-33 months).. CDC has a poor prognosis compared to non-CDC renal cell carcinoma. Treatment for CDC represents a future challenge and targeted therapies may play a role in selected cases.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides

Limited data are available regarding patients with renal cell carcinoma and ESRD treated with TTs. The objective of this study was to explore the tolerability and safety of TT in patients with mRCC and ESRD.. We retrospectively identified patients with mRCC and ESRD treated at the University of Texas M.D. Anderson Cancer Center from 2002 to 2012. Patient characteristics including demographic, histology, treatment, and adverse events are reported. Duration of treatment (TOT) was determined from date of drug initiation to discontinuation. Overall survival (OS) was determined from initiation of TT to death. Statistics are descriptive.. Fourteen patients were identified. Ten patients had clear-cell histology and 4 had papillary histology. The median number of TTs per patient was 3 (range, 1-4) with median TOT of 28 months for all TTs. Eighty-eight percent of all toxicities were Grade 1 to 2; no Grade 4 toxicities were noted. Treatment discontinuations included 3 patients treated with sorafenib due to hand-foot syndrome, intolerable fatigue, and squamous cell skin cancer development; 2 patients treated with pazopanib due to intolerable fatigue and increased transaminase levels; and 1 patient treated with everolimus due to pneumonitis. Eight patients died from progressive disease. Median OS from initiation of TT was 28.5 months and 35 months from time of diagnosis.. Toxicities were mild to moderate and consistent with those reported in previous studies. TTs appear to be safe, well tolerated and produce antitumor response in patients with mRCC and ESRD receiving dialysis.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Kidney Failure, Chronic; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Renal Dialysis; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Treatment Outcome

Topics: Adult; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Male; Myasthenia Gravis; Neoplasm Recurrence, Local; Prognosis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Uveal Neoplasms

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Patient Preference; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Administration Schedule; Humans; Indazoles; Kidney Neoplasms; Multicenter Studies as Topic; Neoplasm Metastasis; Niacinamide; Patient Selection; Phenylurea Compounds; Pyrimidines; Randomized Controlled Trials as Topic; Sorafenib; Sulfonamides

To evaluate the impact of surgery on the prognosis of metastatic renal cell carcinoma (mRCC) with inferior vena cava (IVC) thrombus.. In this retrospective study, the medical records of 45 patients who presented with synchronous mRCC with IVC thrombus, between 2005 and 2012, were reviewed. Twenty-eight patients underwent radical nephrectomy with IVC thrombectomy followed by targeted therapy (group 1) and 17 received targeted therapy alone (group 2). Cox proportional hazards regression models served to estimate the prognostic significance of variables.. The median progression-free survival of group 1 and group 2 was 4.1 and 3.5 months, respectively (P = 0.672). Their median overall survival was 17.3 and 19.7 months, respectively (P = 0.353). Multivariate analysis revealed that non-clear cell type RCC (HR = 3.46, P = 0.007) and lymph node metastasis (HR = 2.31, P = 0.003) independently predicted progression-free survival, and Karnofsky performance status (HR = 3.82, P = 0.013) and non-clear cell type RCC (HR = 4.01, P = 0.003) independently predicted overall survival. Surgical resection of the primary renal mass with IVC thrombus did not affect the probability of progression or overall mortality.. Our limited data set would suggest a limited role for surgery in this patient population and that a prospective study in this group may define the role of surgery.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplastic Cells, Circulating; Nephrectomy; Niacinamide; Phenylurea Compounds; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Thrombectomy; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

Patients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy.. Patients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented.. Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti-VEGF- and everolimus-treated patients, respectively (P = .021).. In this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Pazopanib is an oral tyrosine kinase inhibitor with demonstrated efficacy and tolerability in patients with advanced renal cell carcinoma (RCC).. To examine pazopanib persistence and compliance (adherence) and other drug utilization patterns in both treatment-naïve (first-line) patients and those previously treated with RCC therapy in the real-world setting. Key factors affecting persistence and compliance were also explored.. This was a retrospective claims analysis using the Truven Health MarketScan Databases to cover claims activity from October 2007 through March 2012. Patients with advanced RCC aged ≥ 18 years who had received pazopanib with 180 days of follow-up were included. Bivariate comparisons of results from first-line and previously treated patients with RCC were conducted. Pazopanib persistence was measured using (a) estimated level of persistence with therapy (ELPT; i.e., the percentage of patients remaining on therapy at 30, 60, and 90 days [patients were censored at 180 days]); (b) time to discontinuation (i.e., duration of therapy); and (c) proportion of days covered (PDC; i.e., the ratio of [total days drug available minus days' supply of last prescription] to [last prescription date minus first prescription date]). Compliance was measured by medication possession ratio (MPR; i.e., the ratio of [total days' supply minus days' supply of last prescription] to [last prescription date minus first prescription date]). Other drug utilization measures included days' supply, time to initiation, time to switching, and dose-related measures. Random forest models were used to explore key factors of pazopanib persistence and compliance.. A total of 143 patients met all inclusion criteria; 43.3% were treated with pazopanib first line (first-line cohort), and 56.6% had ≥ 1 prior lines of therapy (previously treated cohort). The mean (± standard deviation [SD]) age of patients was 62.9 (± 10.3) years, and 71.3% of them were males. Continuous pazopanib therapy for up to 90 days was observed in greater than 50% of patients in both cohorts. In the first-line cohort, ELPT at 30, 60, and 90 days was 98.39%, 70.97%, and 56.45%, respectively; the mean (± SD) number of days to discontinuation was 112.2 (± 62.8); the mean (± SD) PDC was 84.7% (± 16.7%); and the mean (± SD) MPR was 85.2% (± 16.9%). Similar results were observed in the previously treated population: ELPT at 30, 60, and 90 days was 98.77%, 75.31%, and 58.02%, respectively; the mean (± SD) number of days to discontinuation was 118.7 (± 61.4); the mean (± SD) PDC was 87.8% (± 13.5%); and the mean (± SD) MPR was 90.1% (± 13.9%). Differences between the 2 cohorts were not statistically significant. More than 90% of patients in both cohorts had at least a 30-day supply of therapy (91.9% of first-line versus 90.2% of previously treated; P = 0.153). The mean (± SD) time from metastatic diagnosis to start of pazopanib therapy was 104.7 (± 199.3) days in the first-line cohort and 360.9 (± 187.0) days in previously treated patients (P = 0.001). Forty-six patients switched to another therapy: 17 patients in the first-line cohort and 29 patients in the previously treated cohort; the mean (± SD) time to switching therapy from each cohort was 94.7 (± 41.4) days and 87.8 (± 49.6) days (P = 0.146), respectively. Statistically significant differences were observed for the starting and ending doses between the 2 cohorts. The average daily dosage of pazopanib was greater than 700 mg in both cohorts (P = 0.055), with a maximum dose of 800 mg. Random forest models demonstrated that younger age and higher comorbidity predicted both higher persistence and compliance.. In this observational study, greater than 50% of patients with advanced RCC were on pazopanib for almost 4 months, with the majority of both cohorts achieving high persistence and high compliance. Additionally, younger age and higher comorbidity index were the strongest predictors of both greater persistence and compliance. Further studies with larger cohorts and longer follow-up are needed to validate these findings.

Topics: Age Factors; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Comorbidity; Databases, Factual; Drug Prescriptions; Drug Utilization Review; Female; Humans; Indazoles; Insurance Claim Reporting; Kidney Neoplasms; Male; Medication Adherence; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Time Factors; Treatment Outcome; United States

This study aimed to assess the efficacy of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKIs) in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) with sarcomatoid dedifferentiation.. The files of all patients with m-ccRCC consecutively treated with first-line anti-VEGFR-TKIs at the authors' institution were retrospectively reviewed. Pathology slides from nephrectomy and metastasectomy were assessed for the presence and extent of sarcomatoid dedifferentiation.. A total of 124 patients were included; nephrectomy and metastasectomy specimens were available in 117 and 35 patients, respectively. Thirty percent of the primary nephrectomy specimens had sarcomatoid features, and the median involvement of the sarcomatoid component was 21% (range, 1%-95%). Patients with an important sarcomatoid component, defined as ≥ 25% involvement of the tumor, had a very poor outcome: progression-free survival (PFS) and overall survival (OS) were 3 and 6 months, respectively, and no partial responses (PR) were observed. Patients without sarcomatoid dedifferentiation or with sarcomatoid involvement < 25% had a PFS of 12 months (P < .0001; hazard ratio [HR], 51; 95% CI, 12.58-207.3), an OS of 22 months (P < .0001, HR, 10.72; 95% CI, 3.56-32.25), and a PR rate of 50% (P = .0015). Patients with a sarcomatoid component ≥ 25% in the metastasectomy also had a poorer PFS and OS on anti-VEGFR-TKIs compared with patients with < 25% of sarcomatoid features at these sites.. Patients with m-ccRCC whose tumors contain a component of sarcomatoid dedifferentiation of ≥ 25% of the total tumor volume have a very poor outcome when treated with anti-VEGFR-TKIs. Analysis of the extent of sarcomatoid features in resected metastases can provide additional prognostic information.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Cell Differentiation; Disease-Free Survival; Female; Humans; Imidazoles; Indazoles; Indoles; Kidney; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

The prognostic significance of the neutrophil-to-lymphocyte ratio for progression free survival in patients with metastatic renal cell carcinoma is unclear.. We retrospectively reviewed 45 patients diagnosed with metastatic RCC previously treated with tyrosine kinase inhibitors from two centers, Akdeniz University Hospital and Afyon Kocatepe University. The prognostic value of the pretreatment neutrophil- tolymphocyte ratio, and other clinical and laboratory parameters were assessed by univariate and multivariate analysis.. Median progression free survival (PFS) was 13.9 months [95% CI for HR (6.88-20.91)] and overall survival figure of 16.6 months [95% CI for HR (7.23-26.03)] Univariate analysis revealed that PFS was significantly affected by hemoglobin level [p=0.013 (95% CI for HR (0.71-0.96))], eosinophil count [p=0.031 (95% CI for HR (0.20-0.92))], ratio of neutrophil lymphocytes (NLR) [p=0.007 (95% CI for HR (1.47-11.74))] and calcium level [p=0.006 (95% CI for HR (0.15-0.73))]. However, only NLR [p=0.031 (95% CI for HR (1.15- 18.1))] and calcium levels [p=0.018 (95% CI for HR (0.20-18.1))] retained significance with multivariate analysis. Median PFS was 23.9 vs 8.6 months in patients with NLR ≤ 2 vs NLR >2 (Log rank; p= 0.040).. This study showed that increased pretreatment NLR is an independent prognostic factor for patients with metastatic RCC using tyrosine kinase inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Disease-Free Survival; Eosinophils; Female; Hemoglobins; Humans; Indazoles; Indoles; Kidney Neoplasms; Leukocyte Count; Lymphocyte Count; Male; Middle Aged; Multivariate Analysis; Neutrophils; Niacinamide; Phenylurea Compounds; Prognosis; Proportional Hazards Models; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib

Combination of immunotherapy with tyrosine kinase inhibitors (TKIs) has been used with some success for the treatment of metastatic renal cell carcinoma. Herein we evaluate the in vitro effect of high-dose interleukin-2 (HDIL-2) and pazopanib or sunitinib on the lymphocyte function and on induction of apoptosis in renal cell carcinoma (RCC) cell lines.. Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors or RCC patients were treated with different HDIL-2/TKI combinations. Effects of different combinations on proliferation and cytotoxic activity of PBMCs were evaluated, in addition to their effect on apoptosis of three different RCC cell lines.. While sunitinib did not inhibit the proliferation of various immune cells induced by HDIL-2, pazopanib appeared to inhibit the HDIL-2-induced proliferation of these cells. Interestingly, none of the HDIL-2/TKI combinations appeared to compromise the functional properties of these cells. Additionally, significant proportion of RCC cell lines treated with pazopanib alone underwent apoptosis, while the proportions of apoptotic cells post-HDIL-2 or sunitinib were not different from the background. Furthermore, the combination of HDIL-2/pazopanib did not inhibit the pazopanib-induced RCC apoptosis.. The combination of HDIL-2 with either pazopanib or sunitinib exerts different anticancer mechanisms that could enhance the treatment efficacy.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Lymphocytes; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

To determine whether changes in the metabolism of metastatic renal cell carcinoma (mRCC) assessed by F18-FDG-PET after 14 and 28 days of treatment with tyrosine kinase inhibitors can predict overall and progression- free patient survival.. Thirty-nine consecutive patients with mRCC were included prospectively and underwent PET examinations prior to and after 14 and 28 days of standard treatment with sunitinib (n=18), sorafenib (n=19) or pazopanib (n=2). The PET response was analyzed in terms of SUVmax, SULpeak, and total lesion glycolysis and a positive response (defined as a 30% reduction) compared to overall and progression- free survival.. Thirty-five patients with at least one metabolically active metastatic lesion prior to treatment underwent additional FDG-PET examinations after 14 (n=32) and/or 28 days (n=30) of treatment. Changes in either SULpeak or total lesion glycolysis were correlated to both progression-free and overall survival (for TLG2.5 responders, HR=0.38 (95% CI: 0.18-0.83) and 0.22 (95% CI: 0.09-0.53), and for TLG50 responders, HR=0.25 (0.10-0.62) and 0.25 (95% CI: 0.11-0.57) and for SULpeak responders, HR=0.39 (95% CI: 0.17-0.91) and 0.38 (95% CI: 0.15-0.93), respectively). In contrast SUVmax response did not predict progression- free or overall survival (HR=0.43 (95% CI: 0.18-1.01) and 0.50 (95% CI: 0.21-1.19), respectively).. Assessment of early changes in SULpeak and total lesion glycolysis undergoing treatment with tyrosine kinase inhibitors by FDG-PET can possibly predict progression- free and overall survival in patients with mRCC.

Topics: Aged; Carcinoma, Renal Cell; Cone-Beam Computed Tomography; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Positron-Emission Tomography; Prognosis; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib; Treatment Outcome

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Eruptions; Humans; Indazoles; Kidney Neoplasms; Lupus Erythematosus, Cutaneous; Male; Pyrimidines; Sulfonamides

Topics: Aged; Angiogenesis Inhibitors; Axitinib; Carcinoma, Renal Cell; Female; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Neoplasm Recurrence, Local; Prognosis; Pyrimidines; Radiography; Spinal Neoplasms; Sulfonamides

Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC).. Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries.. Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 μg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range.. The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

Topics: Angiogenesis Inhibitors; Biomarkers, Tumor; Blood Pressure; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Follow-Up Studies; Humans; Indazoles; Kidney Neoplasms; Neoplasm Staging; Prognosis; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Survival Rate; Tissue Distribution; Vascular Endothelial Growth Factor Receptor-2

This article describes the lessons learned from an international pilot assessment using the first version of the HTA Core Model® and Guidelines for rapid Relative Effectiveness Assessment (REA) of pharmaceuticals based on input from three different perspectives: the assessors, the users (health technology assessment organisations) and the marketing authorisation holder.. A pilot assessment was performed of pazopanib for the treatment of advanced or metastatic renal cell carcinoma for which 54 individuals from 22 EUnetHTA member organisations from 16 European countries gave their contribution. The work was divided in eight domain teams. Subsequently, results of these domain teams were synthesised in one pilot report. Feedback on the outcomes of the pilot was gathered throughout the project and through structured surveys.. The first version of the assessment was produced in six months and consisted of 55 question and answer pairs, 8 domain reports and a synthesis section that combined the results from the different domains. The organisation of the pilot required intense coordination. Main points of criticism on the assessment were the lengthiness of the document and overlap of information throughout the assessment.. A reduction in the number of authoring organisations and individuals participating is necessary to avoid information overlap and increase efficiency in undertaking the assessment. Involving several organisations (e.g. five) in an in-depth review could still ensure the benefit of broad participation from various countries. The focus of a rapid REA should be on the first four domains of the Model.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Comparative Effectiveness Research; Europe; Humans; Indazoles; International Cooperation; Kidney Neoplasms; Pilot Projects; Program Evaluation; Prohibitins; Pyrimidines; Sulfonamides; Surveys and Questionnaires; Technology Assessment, Biomedical

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides

We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens.. Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus.. Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo.. Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Female; Gene Expression; Humans; Indazoles; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Molecular Targeted Therapy; Pyrimidines; Pyrroles; Sirolimus; Stearoyl-CoA Desaturase; Sulfonamides; Sunitinib; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays

To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT).. A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT.. Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM examination (cohort B). In these patients, no ONJ was observed. Nine patients received ZA and TT and pretherapy OM examination (cohort C). One patient (11%) developed ONJ during sunitinib and ZA treatment. Mean skeletal morbidity rates were 0.8 for cohort A and 1.2 for cohort C. In the combined cohort (A plus C; n = 30), 47% developed skeletal-related events, 7% pathologic fracture, 7% medullary compression, and 37% progression of bone metastases. Patients who developed ONJ had a significantly improved median survival of 31.6 months compared with 14.5 months in patients without ONJ (P = .039).. The combination of ZA and TT resulted in high, clinically meaningful activity. ONJ may be exacerbated by concomitant ZA and sunitinib. Regular OM examinations before and during treatment are recommended.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma, Renal Cell; Cohort Studies; Diphosphonates; Everolimus; Female; Follow-Up Studies; Fractures, Spontaneous; Humans; Imidazoles; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Radiography, Panoramic; Retrospective Studies; Sirolimus; Sorafenib; Spinal Cord Compression; Sulfonamides; Sunitinib; Survival Rate; Zoledronic Acid

The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited.. We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods.. Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths.. Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides

We examine how changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy.. In metastatic renal cancer patients treated with anti-angiogenic tyrosine kinase inhibitors, arterial phase contrast-enhanced computed tomography was used to simultaneously measure changes in: (a) tumour size, and (b) tumour enhancement (a surrogate marker of tumour vessel density) within individual lesions.. No correlation between baseline tumour enhancement and lesion shrinkage was observed, but a reduction in tumour enhancement on treatment was strongly correlated with reduction in lesion size (r=0.654, P<0.0001). However, close examination of individual metastases revealed different types of response: (1) good vascular response with significant tumour shrinkage, (2) good vascular response with stabilisation of disease, (3) poor vascular response with stabilisation of disease and (4) poor vascular response with progression. Moreover, contrasting responses between different lesions within the same patient were observed. We also assessed rebound vascularisation in tumours that acquired resistance to treatment. The amplitude of rebound vascularisation was greater in lesions that had a better initial response to therapy (P=0.008).. Changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. The data provide insight into the mechanisms that underlie response and resistance to this class of agent.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Biomarkers, Tumor; Blood Vessels; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sulfonamides; Sunitinib

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Colchicine; Drug Therapy, Combination; Gout; Gout Suppressants; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

Due to economic constraints, cancer therapies are under close scrutiny by clinicians, pharmacists and payers alike. There is no published pharmacoeconomic evidence guiding the choice of first-line therapy for advanced renal cell carcinoma (RCC) in the Spanish setting. We aimed to develop a model describing the natural history of RCC that can be used in healthcare decision-making. We particularly analyzed the budget impact associated with the introduction of pazopanib compared to sunitinib under the Spanish National Healthcare System (NHS) perspective.. We developed a Markov model to estimate the future number of cases of advanced RCC (patients with favorable or intermediate risk) resulting either from initial diagnosis or disease progression after surgery. The model parameters were obtained from the literature. We assumed that patients would receive either pazopanib or sunitinib as first-line therapy until disease progression. Pharmacological costs and costs associated with the management of adverse events (AE) were considered. A univariate sensitivity analysis was undertaken in order to test the robustness of the results.. The model predicted an adult RCC prevalence of 7.5/100,000 (1-year), 20.7/100,000 (3-year) and 32.5/100,000 (5-year). These figures are very close to GLOBOCAN reported RCC prevalence estimates of 7.6/100,000, 20.2/100,000 and 31.1/100,000, respectively. The model predicts 1,591 advanced RCC patients with favorable or intermediate risk in Spain in 2013. Annual per patient pharmacological costs were €32,365 and €39,232 with pazopanib and sunitinib, respectively. Annual costs associated with the management of AE were €662 and €974, respectively. Overall annual per patient costs were €7,179 (18%) lower with pazopanib compared to sunitinib. For every point increase in the percentage of patients treated with pazopanib, the NHS would save €67,236. If all the 1,591 patients predicted were treated with pazopanib, the NHS would save €6,723,622 in 2013. Results were robust according to the sensitivity analysis.. We developed a model that accurately reproduces the natural history of RCC and can be thus used in healthcare decision-making. When applied to the Spanish case, the introduction of pazopanib results in savings for the NHS, as a consequence of both reduced pharmacological costs and lower costs associated with the management of AE compared to sunitinib.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Cost-Benefit Analysis; Decision Making, Organizational; Health Care Costs; Humans; Incidence; Indazoles; Kidney Neoplasms; Markov Chains; Neoplasm Staging; Prevalence; Pyrimidines; Spain; Sulfonamides

Pazopanib, a tyrosine kinase inhibitor, is one of the new registered first-line therapeutic options in the treatment of metastatic clear cell renal carcinoma. Our aim was to evaluate the efficiency and toxicity of first-line pazopanib therapy administered for patients with metastatic clear cell renal carcinoma with good- and medium prognosis according to MSKCC criteria. Between January and May, 2011, 24 patients have been treated with pazopanib in 8 oncology centers in Hungary, out of them 21 patients' data were analyzed. The mean age was 65.3 (49-81) years, 10 males and 11 females. According to MSKCC the prognosis was good and medium in 3 and 18 cases, respectively. Daily dose of pazopanib was 800 mg administered continuously in 28 day cycles. Dose reduction was performed according to the instructions of the registration study. Tumor response was evaluated according to RECIST 1.0. Currently 6 (28.6%) patients are on treatment. Dose reduction was necessary in 6 (28.6%) cases with an average duration of 14.55 (7-150) days. Mean±SE daily dose was 692.97±13.67 (400-800) mg. Median PFS was 12.41 months (95% CI 11.52-12.94 months). Complete remission (CR), as the best tumor response occurred in 2 (9.5%) cases. Partial remission (PR), stable disease (SD) and progression was observed in 6 (28.6%), 10 (47.6%) and 3 (14.3%) cases, respectively. Objective tumor response was observed in 8 pts (38%). Median survival could not be statistically analyzed yet due to the insignificant number of fatal outcomes. Median follow-up was 25.22 months (95% CI 2.47-28.1 months). As common side-effect fatigue, weakness and diarrhea occurred in 11 (52.4%), 9 (42.9%) and 8 (38%) cases, respectively. Besides these, worsening of high blood pressure and ALT/AST elevation was observed in 5 (23.8%) and 6 (28.6%) cases, respectively. Based on the initial Hungarian experiences, pazopanib is a well tolerable product and can be administered safely. According to our results its efficiency in terms of tumor response and progression-free survival is comparable to the results of the registration study.. Az áttétes világossejtes veserák egyik új, törzskönyvezett készítménye a pazopanib. Célunk az MSKCC jó és közepes prognózisú, metasztatikus világossejtes veserákos betegek elsõ vonalbeli pazopanibterápiája hatékonysági és toxicitási profiljának értékelése volt. 2011. január és május között hazánk 8 onkológiai centrumában 24 betegnél indult pazopanibkezelés, közülük 21 adatait elemeztük. Átlagéletkoruk 65,3 (49–81) év, 10 férfi, 11 nõ, MSKCC szerint 3 jó, 18 közepes prognózisú. A pazopanib dózisa 800 mg volt naponta, 28 napos ciklusokban. A tumorválasz értékelése a RECIST 1.0 szerint történt. 6 (28,6%) beteg kezelése folya matban van. Dóziscsökkentés 6 (28,6%) betegnél történt, átlagosan 14,55 (7–150) nap idõtartamban. Az átlagos napi dózis±SE 692,97±13,67 (400–800) mg. A progressziómentes túlélés medián 12,41 hónap. Komplett remisszió 2 (9,5%), részleges remisszió 6 (28,6%), stabil betegség 10 (47,6%) esetben alakult ki, 3 (14,3%) progressziót észleltünk. Objektív tumorválaszt 8 fõnél (38%) észleltünk. A medián teljes túlélés statisztikailag nem értékelhetõ a kis számú halálozási esemény miatt. A betegek követésének medián idõtartama 25,22 hónap. Leggyakoribb mellékhatások a fáradékonyság 11 (52,4%), gyengeség 9 (42,9%), hasmenés 8 (38%), magas vérnyomás kialakulása/romlása 5 (23,8%), valamint ALT/AST emelkedés 6 (28,6%). A kezdeti hazai tapasztalatok alapján a pazopanib biztonsággal alkalmazható. Hatékonysága a tumorválasz és a progressziómentes túlélés szempontjából hasonló a törzskönyvezõ vizsgálat eredményeihez.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Diarrhea; Disease-Free Survival; Female; Humans; Hungary; Hypertension; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sulfonamides; Treatment Outcome

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Prognosis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides

Predictive biomarkers to guide therapy for cancer patients are a cornerstone of precision medicine. Discussed herein are considerations regarding the design and interpretation of such predictive biomarker studies. These considerations are important for both planning and interpreting prospective studies and for using specimens collected from completed randomized clinical trials. Specific issues addressed are differentiation between qualitative and quantitative predictive effects, challenges due to sample size requirements for predictive biomarker assessment, and consideration of additional factors relevant to clinical utility assessment, such as toxicity and cost of new therapies as well as costs and potential morbidities associated with routine use of biomarker-based tests.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Dacarbazine; DNA Modification Methylases; DNA Repair Enzymes; ErbB Receptors; Gefitinib; Glioblastoma; Humans; Indazoles; Interleukin-6; Kidney Neoplasms; Lung Neoplasms; Methylation; Molecular Targeted Therapy; Mutation; Neoplasms; Precision Medicine; Predictive Value of Tests; Pyrimidines; Quinazolines; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Sample Size; Sulfonamides; Temozolomide; Tumor Suppressor Proteins

Pazopanib is a multi-targeted tyrosine kinase inhibitor that has recently been approved for treatment of advanced clear cell renal cell carcinoma (RCC). There are no previous reports of pazopanib triggering radiation recall dermatitis (RRD).. A 60-year-old male patient was commenced on pazopanib for metastatic RCC 2 weeks prior to receiving radiotherapy (10×30 Gy) to bone metastases at the T9 and L4 vertebrae and right mid-shaft of humerus. Although there were no immediate complications from radiotherapy, 2 weeks after finishing radiation he developed a pruritic, erythematous, maculo-papular rash localized to the T9 and right humeral radiotherapy fields. The patient was diagnosed with RRD induced by pazopanib and commenced on a course of oral prednisolone, which resulted in resolution of his rash. He has now completed 5 months of pazopanib with no recurrence of RRD.. We report the first case of RRD triggered by pazopanib. With increasing use of pazopanib for advanced RCC, clinicians must be aware of the possibility that RRD can occur in patients treated with this agent following radiotherapy.

Topics: Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Radiodermatitis; Radiotherapy, Conformal; Sulfonamides; Treatment Outcome

Posterior reversible encephalopathy syndrome (PRES) can be the result of acute hypertension, eclampsia, renal failure and the use of immunosuppressive or cytotoxic agents. We report a case of PRES as a result of the use of pazopanib, a vascular endothelial growth factor inhibitor used for renal cell carcinoma (RCC).. A 76-year-old man treated with RCC develops PRES shortly after the initiation of pazopanib.. There are no known reports of the association between PRES and pazopanib. We postulate that pazopanib can disrupt the normal endothelial function of the brain leading to the development of PRES.

Topics: Aged; Carcinoma, Renal Cell; Humans; Immunosuppressive Agents; Indazoles; Kidney Neoplasms; Male; Posterior Leukoencephalopathy Syndrome; Pyrimidines; Sulfonamides; Vascular Endothelial Growth Factor A

Limited information on real-world treatment patterns of targeted agents for metastatic renal cell carcinoma (mRCC) is available to inform their use in clinical practice.. This retrospective observational study used US claims data (from January 2007 to November 2010) to identify treatment patterns, including treatment duration and dosing, for molecular-targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab, and temsirolimus) indicated in first-line management of advanced and/or mRCC. The study included adult patients with mRCC who were observable for ≥3 months after initiation of their first-line therapy with a targeted agent. Descriptive analyses were conducted for observed treatment patterns.. Of the 273 patients on first-line therapy identified and included in the sample, 235 patients were treated with sunitinib, 16 patients with sorafenib, and 15 patients with temsirolimus. Pazopanib and bevacizumab were excluded from the analysis due to the small sample size, n < 10. The median observed treatment durations were sunitinib 98 days, sorafenib 121 days, and temsirolimus 78 days. Approximately 76% (178/235) of patients who received sunitinib initiated therapy at the indicated dose of 50 mg; 65% of these patients were not observed filling a fourth prescription, whereas 23% maintained their starting dose and 12% experienced dose reduction at their 4+ fill. The mean starting dose for patients who initiated on sorafenib (n = 16) was 725 mg and for temsirolimus (n = 15) was 25 mg: their study samples were insufficient for further, meaningful dosing analyses.. Results of this study suggest that opportunities exist to improve treatment duration in clinical practice and to better understand influences on treatment and dose changes.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cohort Studies; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; United States

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

To provide an updated review of adverse events associated with sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus and sorafenib and their management.. We performed a PubMed and Cochrane-based review of side effects associated with the seven agents including product monographs to provide an outline of treatment measures aiming to reduce their toxicities. Subject and outcome of interest, design type, sample size, pertinence and quality, and detail of reporting were the indicators of manuscript quality.. All targeted therapies cause adverse events. Most adverse events may be prevented or tested before they escalate to severe levels.. Prevention, early recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Disease Progression; Drug Administration Schedule; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Nephrectomy; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Treatment Outcome

Temsirolimus is a standard of care in patients with metastatic renal cell carcinoma (mRCC) with poor risk factors. The role of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) remains poorly defined in this setting.. Records of our center were examined to identify patients with mRCC and 3 or more poor prognosis factors, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, who had been treated with VEGFR TKIs. Their baseline characteristics, radiologic response, adverse events, and survival status were assessed.. The 88 patients who met our inclusion criteria had a median age of 56 years (range 17-83 years). We observed clear cell histology in 71 (81%) patients, and 52 (59%) underwent prior nephrectomy. Seventy-six patients (86%) were treated with sunitinib and 10 (11%) with sorafenib. Of 85 patients with measurable lesions, 19 (22%) showed objective response, with disease control achieved in 49 (56%). At a median follow-up of 29.6 months, the median time to progression was 5.0 months (95% CI, 3.5-6.5 months) and the median overall survival (OS) was 9.3 months (95% CI, 7.1-11.5 months). Neutrophil count (>ULN), bone metastasis, and lymph node metastasis were independent prognostic factors for OS, whereas prior nephrectomy was not.. VEGFR TKIs, especially sunitinib, are active and tolerated by mRCC patients with poor risk features.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Drug Administration Schedule; Fatigue; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Thrombocytopenia; Treatment Outcome; Young Adult

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Prognosis; Pyrimidines; Pyrroles; Retreatment; Sulfonamides; Sunitinib

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Topics: Angiogenic Proteins; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cytokines; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

Several targeted drugs are approved for treatment of patients with metastatic renal-cell cancer, but no validated biomarkers are available for prediction of clinical outcome. We aimed to assess the prognostic and predictive associations of pretreatment plasma concentrations of cytokine and angiogenic factors (CAFs) with data from a phase 2 and a phase 3 trial of pazopanib treatment.. We used a three-step approach for screening, confirmation, and validation of prospective CAF biomarkers. We screened 17 CAFs in 129 patients who had the greatest or least tumour shrinkage in a phase 2 trial of 215 patients treated with pazopanib. We confirmed associations of candidate CAFs (those identified in the screening and from previous studies) with tumour response and progression-free survival (PFS) in 215 patients from this phase 2 trial with an independent analytical platform. We validated confirmed markers in 344 patients from a randomised, placebo-controlled, phase 3 clinical study of pazopanib.. Five candidate markers emerged from initial screening-interleukin 6, interleukin 8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analyses identified associations of interleukin 6, interleukin 8, VEGF, osteopontin, E-selectin, and HGF with continuous tumour shrinkage or PFS in patients treated with pazopanib. In the validation set of samples from the phase 3 trial, patients treated with pazopanib who had high concentrations (relative to median) of interleukin 8 (p=0·006), osteopontin (p=0·0004), HGF (p=0·010), and TIMP-1 (p=0·006) had shorter PFS than did those with low concentrations. In the placebo group, high concentrations of interleukin 6 (p<0·0001), interleukin 8 (p=0·002), and osteopontin (p<0·0001) were all prognostically associated with shorter PFS. These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High concentrations of interleukin 6 were predictive of improved relative PFS benefit from pazopanib compared with placebo (p(interaction)=0·009); standard clinical classifications were not predictive of PFS benefit.. CAF profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal-cell carcinoma. Further studies of the predictive effects of these markers in different populations and with different drugs (eg, mTOR inhibitors) are warranted.. GlaxoSmithKline.

Topics: Angiogenic Proteins; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cluster Analysis; Cytokines; Disease-Free Survival; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Linear Models; Logistic Models; Multicenter Studies as Topic; Predictive Value of Tests; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Sulfonamides; Time Factors; Treatment Outcome; Tumor Burden

Topics: Aged; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Vascular Endothelial Growth Factor A

The reversible posterior leukoencephalopathy syndrome is a clinical/radiological syndrome characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging findings. There are several reports in the literature that depict its occurrence in cancer patients. The list of common anticancer and supportive care drugs that predispose to reversible posterior leukoencephalopathy syndrome is expanding and includes not only a large number of chemotherapeutic agents but also an increased number of new targeted drugs, particularly angiogenesis inhibitors such as bevacizumab,sorefenib and sunitinib. Pazopanib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit which after a positive phase III randomized clinical trial in patients with advanced renal cell cancer received FDA approval for the treatment of advanced renal cell carcinoma. Until now no cases of reversible posterior leukoencephalopathy syndrome induced by pazopanib have been reported.. We present the case of a 40 years old female patient with heavily pre-treated metastatic renal cell carcinoma who received pazopanib as salvage treatment. After 21 days of pazopanib therapy the patient referred to the emergency department with epileptic seizure, impaired vision at both eyes and headache. MRI of the brain revealed subcortical oedema at the occipital and parietal lobes bilaterally. She was treated with anticonvulsants, i.v. administration of mannitol and antihypertensives and she recovered completely from her symptoms and was discharged on the tenth hospital day. A brain MRI performed 3 weeks after showed that the subcortical oedema had been subsided.. In conclusion this is the first case of pazopanib induced reversible posterior leukoencephalopathy syndrome. Although usually reversible, this syndrome is a serious and potentially life threatening adverse effect, if untreated, that should be considered by physicians treating metastatic renal cell carcinoma patients with pazopanib.

Topics: Adult; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Posterior Leukoencephalopathy Syndrome; Pyrimidines; Sulfonamides

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways.. Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively.. Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%).. Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Cross-Over Studies; Disease-Free Survival; DNA Mutational Analysis; Genetic Markers; Genotype; Germ-Line Mutation; Humans; Indazoles; Kidney Neoplasms; Multicenter Studies as Topic; Neoplasm Proteins; Neovascularization, Physiologic; Polymorphism, Single Nucleotide; Proportional Hazards Models; Pyrimidines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Sulfonamides

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Cooperative Behavior; Cytokines; Disease Progression; Everolimus; Evidence-Based Medicine; Humans; Indazoles; Indoles; Interdisciplinary Communication; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Patient Care Team; Phenylurea Compounds; Platelet-Derived Growth Factor; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Signal Transduction; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Differentiation; Female; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

We examined the in vitro cellular effects of the multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib on a series of human renal cell carcinoma (RCC) cell lines.. The human RCC cell lines 769-P, 786-O, HRC-24, HRC-31, HRC-45, HRC-78, SK-26B, and SK-45 were treated with varying concentrations of sunitinib and pazopanib. Cellular proliferation and cellular death were assessed using the CellTiter-Blue Cell Viability Assay and the TUNEL assay, respectively. Effective doses (ED) for inhibition of cellular proliferation or induction of apoptosis were calculated for sunitinib and pazopanib in each RCC cell line.. Both sunitinib and pazopanib exhibited anti-proliferative activity to varying degree against all human RCC cell lines; however, sunitinib's effects were achieved at significantly lower concentrations. Moreover, sunitinib had a direct pro-apoptotic effect on all tested cell lines, while pazopanib failed to induce apoptosis in any of the examined human RCC cell lines even at maximal concentrations.. Although sunitinib and pazopanib are often used interchangeably in the clinical setting, our results suggest that in-vitro biological activity of the two agents differs. Sunitinib exhibits a cytotoxic effect on RCC cell lines, while pazopanib's activity is solely cytostatic. These data may be clinically relevant given the current lack of comparative in-vivo studies between the two agents.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Indazoles; Indoles; Kidney Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Sulfonamides; Sunitinib

The rapid evolution of targeted therapies has had a dramatic impact on multiple domains in oncology, particularly metastatic renal cell carcinoma (RCC). Four agents antagonizing vascular endothelial growth factor-mediated signaling have been approved for the treatment of metastatic RCC, including the monoclonal antibody bevacizumab and the small molecular inhibitors sunitinib, sorafenib, and pazopanib. Pazopanib was approved in 2009 for this disease on the basis of a phase III clinical trial demonstrating a superior progression-free survival compared to placebo in 435 patients with either treatment-naive or cytokine-refractory disease. The trial offered insight related to the toxicity profile associated with this agent. The most common clinical adverse events are diarrhea, hypertension, nausea, anorexia, and vomiting. With respect to laboratory adverse events, hepatotoxicity represents a specific concern with pazopanib. Oncology nurses play a critical role in counseling patients regarding the toxicity profile and management of adverse events in pazopanib treatment.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Indazoles; Kidney Neoplasms; Nursing Methodology Research; Oncology Nursing; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

In October 2009, pazopanib (Votrient; GlaxoSmithKline)--a multikinase inhibitor with targets that include vascular endothelial growth factor receptors--was approved by the US FDA for the treatment of advanced renal cell carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Delivery Systems; Humans; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Drug Delivery Systems; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome; Vascular Endothelial Growth Factors

Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction.. Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study.. No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3-32.2) compared with other genotypes.. The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

Topics: Aged; Alanine Transaminase; Antineoplastic Agents; Bilirubin; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Genotype; Gilbert Disease; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Indazoles; Kidney Neoplasms; Liver; Male; Middle Aged; Nephrectomy; Polymorphism, Genetic; Pyrimidines; Sulfonamides

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Interactions; Everolimus; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sirolimus; Sulfonamides

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Topics: Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Protein Serine-Threonine Kinases; Pyrimidines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Sulfonamides; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Several years ago, the oncologist was limited to a narrow scope of immunotherapeutic agents for the treatment of metastatic renal cell carcinoma (mRCC). Within the past 5 years, however, a total of 6 targeted agents have been approved for the treatment of this disease. The abundance of novel therapies has introduced a new dilemma for the oncologist--namely, how can one make evidence-based choices amongst available agents? Recently, two Phase III studies (AVOREN and Cancer and Leukemia Group B [CALGB] 90206) assessed the activity of 1st-line therapy with bevacizumab in combination with interferon-alfa (IFN-alfa) as compared to IFN-alfa alone. Both trials demonstrated a significant benefit in progression-free survival (PFS) with bevacizumab, with no benefit in overall survival (OS). Herein, the implications of these data are assessed in the context of data reported from other recent pivotal trials in mRCC. Methods to resolve areas of clinical equipoise in the treatment of mRCC (i.e., comparative trial designs and biomarker analyses) are also proposed.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Multicenter Studies as Topic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis