cabozantinib and lenvatinib

Tyrosine kinase inhibitors (TKI) or immune checkpoint blockade (ICB), either alone or in combination, confers a significant overall survival (OS) benefit for metastatic RCC in the first-line setting. However, guidance for optimal treatment selection in elderly patients remains limited.. A database search was performed to identify eligible randomized controlled trials (RCTs) evaluating first-line regimens for patients with advanced RCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and OS. Indirect comparisons of available regimens were estimated using a random-effects network meta-analysis.. A total of 14 and five RCTs were eligible for PFS and OS analyses. Compared with sunitinib, pembrolizumab plus axitinib (HR 0.68, 95% CI 0.48-0.97) and pembrolizumab plus lenvatinib (HR 0.61, 95% CI 0.4-0.94) were associated with improved OS. Pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and cabozantinib alone each showed improved PFS over sunitinib. Among these, pembrolizumab plus lenvatinib showed better PFS than pembrolizumab plus axitinib (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared to nivolumab plus cabozantinib (HR 0.63, 95% CI 0.39-1.03) and cabozantinib alone (HR 0.84, 95% CI 0.40-1.77). Network ranking showed pembrolizumab plus lenvatinib provided the favored OS and PFS benefit for elderly patients.. The combination of ICB with TKI such as pembrolizumab plus lenvatinib needs to be considered over monotherapy in the elderly population, but further validation using real-world data or prospective trials is necessary to confirm the efficacy and safety of first-line regimens for the geriatric population with advanced RCC.

Topics: Aged; Axitinib; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Network Meta-Analysis; Nivolumab; Sunitinib

The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile.

Topics: B7-H1 Antigen; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Protein Kinase Inhibitors

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Hepatectomy; Humans; Liver Neoplasms; Liver Transplantation; Phenylurea Compounds; Pyridines; Quinolines; Ramucirumab; Retreatment; Sorafenib

To perform a systematic review and network meta-analysis to compare the survival benefit and safety profile of current available second-line treatment options of metastatic renal cell carcinomav.. PubMed, EMBASE, Web of Science, and Cochrane Library were systematically researched for eligible articles which were published before July 20, 2021. Studies comparing overall/progression free survival (OS/PFS), objective response rate (ORR), and/or adverse events (AEs) in patients with metastatic renal cell carcinomav were included.. Nine trials (with 4911 patients) were finally included for final network meta-analysis. Cabozantinib, lenvatinib, and lenvatinib plus everolimus were associated with significantly better PFS, OS, and ORR compared with everolimus, and lenvatinib plus everolimus emerged as the best option. As for grade 3 to 4 AEs, nivolumab showed significantly lower risk of AEs compared with everolimus. Other included treatments were associated with significantly increased risk of AEs. When comprehensively assessed the efficacy and safety of included treatments based on the ranking analysis of PFS, ORR, and grade 3 to 4 AEs, lenvatinib plus everolimus, cabozantinib, and nivolumab showed superior efficacy over other treatments, with relatively lower risk of grade 3 to 4 AEs.. Among all included therapies, Lenvatinib plus everolimus was identified as the most effective treatment approach, with the best PFS, OS, and ORR. nivolumab was associated with decreased incidence of grade 3 to 4 AEs among included treatment therapies. When comprehensively evaluated the efficacy and safety of included treatment options, lenvatinib plus everolimus, cabozantinb, and nivolumab were associated with better survival benefits and lower risk of AEs. Future studies should focus on the direct comparison of different second-line treatment in real-world populations.

Topics: Anilides; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Network Meta-Analysis; Nivolumab; Phenylurea Compounds; Pyridines; Quinolines

Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice.. Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA).. Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection.. Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib; Survival Analysis; Vascular Endothelial Growth Factor A

Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03-0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62-2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06-1.24); PFS_HR: 0.99 (95% CI: 0.82-1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05-1.33); PFS_HR: 0.99 (95% CI: 0.81-1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68-16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16-2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22-1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82-5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0-2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians' decisions.

Topics: Anilides; Antineoplastic Agents; Humans; Network Meta-Analysis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms

Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first-line and second-line treatment options should yield significant improvements in survival.. To summarize the evolving landscape of treatment options for patients with advanced HCC.. We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences.. Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine-kinase inhibitor, was recently shown to have non-inferior survival vs sorafenib and is another first-line treatment option. The tyrosine-kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second-line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population.. There are several first-line and second-line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Disease Progression; Humans; Immunotherapy; Liver Neoplasms; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib; Therapies, Investigational

Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.

Topics: Algorithms; Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib; Treatment Outcome

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

Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.

Topics: Anilides; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinolines; Sorafenib

Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

Topics: Anilides; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Pyridines; Quinolines; Ramucirumab; Sorafenib; Treatment Outcome

The principal advancements in the treatment of hepatocellular carcinoma (HCC) are the use of new systemic treatments, such as lenvatinib in first-line treatment and regorafenib, cabozantinib, and ramucirumab in second-line treatment, because of their benefits in terms of overall survival. In addition, nivolumab as a second-line agent was approved by the US Food and Drug Administration in 2017 based on improved radiological response data. Physicians and patients alike will greatly benefit from this expanded arsenal of treatments once all these new drugs for the treatment of HCC finally become available. Unfortunately, in our review of the available data, we found a conspicuous lack of approved systemic treatments for HCC in the distinct setting of after liver transplantation (LT). Careful evaluation of the clinical trials for approved systemic treatments of HCC is crucial when considering the best options for those with HCC recurrence after LT. Although several first-line or second-line treatments have been shown to be effective for HCC, each of these trials was composed of its own specific populations, and those with HCC recurrence after LT were excluded. We have also summarized from a critical and clinical point of view the issues involved in the management of patients who are candidates for systemic treatment in this era of multiple drugs for the same indication.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Humans; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Nivolumab; Patient Selection; Phenylurea Compounds; Progression-Free Survival; Pyridines; Quinolines; Ramucirumab; Randomized Controlled Trials as Topic

The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.

Topics: Aged; Aged, 80 and over; Anilides; Animals; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Disease Progression; Female; Humans; Liver Neoplasms; Male; Models, Animal; Molecular Targeted Therapy; Pharmacokinetics; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Sorafenib; Treatment Outcome

Topics: Anilides; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Female; Humans; Liver Neoplasms; Male; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridines; Quinolines; Risk Assessment; Sorafenib; Survival Analysis; Treatment Outcome

Portal vein tumour thrombosis is common among patients with advanced hepatocellular carcinoma. Tremendous differences exist in the management of hepatocellular carcinoma with portal vein tumour thrombosis between the east and the west, which derive from heterogeneities in its epidemiology, causes, pathology, comorbidities, prognosis, and other demographics. These divergences between the east and the west are not only caused by hepatocellular carcinoma itself, but are also affected by many variables including social factors, physician preferences, accessibility to costly or novel treatments, and reimbursement schemes. In this Review, we compare and contrast the management of hepatocellular carcinoma with portal vein tumour thrombosis in the east and in the west in terms of systemic and surgical treatments, radiotherapy, transcatheter arterial therapies, and portal vein revascularisation. We conclude that a personalised, data-driven approach to care with active management from a multidisciplinary team, as well as increased communication and collaboration between clinicians and researchers based in east and the west, could help to reduce the differences in management and optimise treatment strategies.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Endovascular Procedures; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Liver Transplantation; Nivolumab; Patient Care Team; Phenylurea Compounds; Portal Vein; Pyridines; Quinolines; Radiotherapy, Adjuvant; Ramucirumab; Sorafenib; Stents; Venous Thrombosis

The approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first- and second-line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.. To summarise the evolving field of systemic therapy of hepatocellular carcinoma.. We reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.. We discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.. The tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib-experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib-experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.

Topics: Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib

The global burden of hepatocellular carcinoma (HCC) is increasing and might soon surpass an annual incidence of 1 million cases. Genomic studies have established the landscape of molecular alterations in HCC; however, the most common mutations are not actionable, and only ~25% of tumours harbour potentially targetable drivers. Despite the fact that surveillance programmes lead to early diagnosis in 40-50% of patients, at a point when potentially curative treatments are applicable, almost half of all patients with HCC ultimately receive systemic therapies. Sorafenib was the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months. New drugs - lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line - have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year; thus, therapeutic breakthroughs are still needed. Immune-checkpoint inhibitors are now being incorporated into the HCC treatment armamentarium and combinations of molecularly targeted therapies with immunotherapies are emerging as tools to boost the immune response. Research on biomarkers of a response or primary resistance to immunotherapies is also advancing. Herein, we summarize the molecular targets and therapies for the management of HCC and discuss the advancements expected in the near future, including biomarker-driven treatments and immunotherapies.

Topics: Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Precision Medicine; Pyridines; Quinolines; Ramucirumab; Sorafenib

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.

Topics: Angiogenesis Inhibitors; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab

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

The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

Topics: Anilides; Axitinib; Fatigue; Humans; Imidazoles; Indazoles; Neoplasms; Odds Ratio; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor

Treatment in metastatic renal-cell carcinoma (mRCC) has evolved tremendously in the last decade. The development of newer targeted agents, like vascular endothelial growth factor inhibitors and immunotherapy have changed the treatment paradigm in mRCC patients. Axitinib and everolimus have been used extensively in patients who progressed on prior antiangiogenic therapy. The newer agents including nivolumab, cabozantinib, and lenvatinib in combination with everolimus have all demonstrated overall survival benefit over everolimus. However, with multiple treatment options, optimal choice and sequencing becomes challenging. This article provides an overview of different therapeutic options available as second-line treatment in patients with mRCC along with future directions.

Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Sorafenib

Clear cell renal cell carcinoma (RCC) is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL loss drives tumor angiogenesis and accounts for the clinical activity of VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs), the first-line standard of care for advanced RCC. Within the last year, three new second-line treatments have received FDA approval for use after anti-angiogenic therapy: the immune checkpoint inhibitor nivolumab, the TKI cabozantinib, and the combination of the TKI lenvatinib and the mTOR inhibitor everolimus. Cabozantinib inhibits VEGFRs, MET, and AXL, kinases that promote tumorigenesis, angiogenesis, metastasis, and drug resistance. Compared with everolimus, cabozantinib has shown statistically significant improvements in the three key efficacy endpoints of overall survival, progression-free survival, and objective response rate in patients with RCC who were previously treated with a VEGFR TKI. Herein, we summarize the translational research and clinical development that led to approval of cabozantinib as second-line therapy in RCC.

Topics: Anilides; Antibodies, Monoclonal; Carcinoma, Renal Cell; Everolimus; Humans; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Translational Research, Biomedical; Von Hippel-Lindau Tumor Suppressor Protein

The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.

Topics: Anilides; Carcinoma, Renal Cell; Cell Cycle Checkpoints; Disease-Free Survival; Humans; Interleukin-2; Molecular Targeted Therapy; Neoplasm Metastasis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Multiple agents, including vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin inhibitors have been approved over the past decade for the treatment of metastatic renal cell carcinoma (mRCC). Here, we focus on nivolumab, cabozantinib, and lenvatinib plus everolimus, agents that have recently emerged with positive clinical data leading to 'Food and Drug Administration approval or pending approval in mRCC. We also review the development of novel agents of interest showing promise in mRCC as part of combination therapy'.. Nivolumab and cabozantinib both offer improved survival over everolimus in the second-line treatment of mRCC. Lenvatinib plus everolimus has similarly shown encouraging survival benefits in a phase II trial for the second-line setting. Novel combinations in mRCC, including dual immune checkpoint blockade, VEGF and programmed death 1 inhibition, VEGF and vaccine therapy, dual angiogenic blockade, and VEGF-directed therapy with nanoparticle-containing camptothecin have shown promising activity in early-phase trials.. Multiple promising agents are available in the treatment of mRCC. The appropriate sequencing of agents in the treatment of mRCC may become further elucidated by future studies that prospectively analyze potential biomarkers to identify patients who will derive the greatest benefit from VEGF, mammalian target of rapamycin, or checkpoint inhibitors.

Topics: Anilides; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Disease Management; Everolimus; Humans; Kidney Neoplasms; Neoplasm Metastasis; Nivolumab; Phenylurea Compounds; Pyridines; Quinolines; Treatment Outcome

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

The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Approval; Drug Design; Humans; Kidney Neoplasms; Neoplasm Metastasis; Nivolumab; Phenylurea Compounds; Pyridines; Quinolines; Receptors, Growth Factor

Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC).

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Humans; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms

Advanced thyroid cancer is not amenable to therapy with conventional cytotoxic chemotherapy. However, newer advances in the understanding of the molecular pathogenesis of different subtypes of thyroid cancer have provided new opportunities for the evaluation of molecularly targeted therapies. This has led to multiple clinical trials using various multi-kinase inhibitors and the subsequent US FDA approval of sorafenib for differentiated thyroid cancer and vandetanib and cabozantinib for medullary thyroid carcinoma. This review provides a summary of the current literature for the treatment of advanced thyroid carcinoma and future directions in this disease.

Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Neuroendocrine; DNA Mutational Analysis; Drug Approval; Humans; Imidazoles; Indazoles; Indoles; MAP Kinase Signaling System; Molecular Targeted Therapy; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Sorafenib; Sulfonamides; Sunitinib; Thyroid Neoplasms; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factor A

New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival.. Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroid-stimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary.. So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Diarrhea; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer.

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Benzamides; Benzenesulfonates; Benzoquinones; Bibenzyls; Boronic Acids; Bortezomib; Depsipeptides; ErbB Receptors; Gefitinib; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Imatinib Mesylate; Imidazoles; Indazoles; Indoles; Lactams, Macrocyclic; Lenalidomide; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Receptor Protein-Tyrosine Kinases; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib; Thalidomide; Thyroid Neoplasms; Valproic Acid; Vorinostat

Substantial paradigm shifts have been recently registered in metastatic renal cell carcinoma (mRCC), with combination therapies including immunotherapy showing unprecedented results. We performed number needed to treat (NNT) and number needed to harm (NNH) analyses to evaluate these approaches in mRCC.. Clinical data of mRCC patients enrolled in four phase III trials were collected. The rates at 6, 12, 18, and 24 months for overall survival (OS), duration of response (DoR), and progression-free survival (PFS) were considered. At 6 months, the number of patients that should be treated to prevent one death with sunitinib was 20 for both pembrolizumab-lenvatinib or axitinib, 14 for nivolumab-cabozantinib, and 50 for nivolumab-ipilimumab. NNT was 100 (at 6 months) or >100 (at 12 and 18 months) for nivolumab-ipilimumab. The combinations reported peculiar and not superimposable safety profiles at the NNH analysis.. Although our results should be interpreted with caution, the analysis provides useful insight into the increasingly compelling interpretation of clinical trials. Immune combinations present clinically meaningful differences in terms of efficacy, with some treatments reporting different results at the NNT and the NNH analyses.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Humans; Ipilimumab; Kidney Neoplasms; Nivolumab; Numbers Needed To Treat; Phenylurea Compounds; Pyridines; Quinolines

RET kinase inhibitors have significant activity in patients with medullary thyroid carcinoma (MTC).. We retrospectively reviewed the electronic medical record for patterns of calcitonin, carcinoembryonic antigen (CEA) and tumor measurement responses in consecutive patients with MTC who received treatment with a RET inhibitor for at least 6 months.. Twenty-six patients who received RET kinase inhibitors for at least 6 months were included. All patients experienced an initial decline in calcitonin; 20 (77%) demonstrated later fluctuations in calcitonin, which spiked above baseline levels in 9 individuals (35%). Twenty of the 22 patients (91%) with elevated CEA experienced a decline with treatment, with 11 individuals (50%) later demonstrating transient fluctuations in CEA, including spikes above baseline in 7 patients (32%). Ten of the 26 patients (38%) also demonstrated short-lived fluctuations in RECIST measurements, including changes of over 20% from nadir values. Vacillations in calcitonin, CEA and measurements often occurred repeatedly in individual patients and did not regularly correlate with each other.. Repeated transient fluctuations in tumor markers and measurements are a characteristic of patients with MTC receiving treatment with RET inhibitors, and such short-term vacillations may not reflect responsiveness over the long term.. NCT00215605; NCT00244972; NCT00121680; NCT00495872.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Female; Humans; Indoles; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins c-ret; Pyridines; Pyrroles; Quinolines; Quinolones; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Neoplasms; Treatment Outcome; Valproic Acid

Despite 4 approved combination regimens in the first-line setting for advanced renal cell carcinoma (aRCC), adverse event (AE) costs data are lacking.. A descriptive analysis on 2 AE cost comparisons was conducted using patient-level data for the nivolumab-based therapies and published data for the pembrolizumab-based therapies. First, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib using data from the CheckMate 214 (median follow-up [mFU]: 13.1 months), CheckMate 9ER (mFU: 12.8 months), and KEYNOTE-426 (mFU: 12.8 months) trials, respectively. Second, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib using data from the CheckMate 214 (mFU: 26.7 months), CheckMate 9ER (mFU: 23.5 months), and KEYNOTE-581 (mFU: 26.6 months) trials, respectively. Per-patient costs for all-cause and treatment-related grade 3/4 AEs with corresponding any-grade AE rates ≥ 20% were calculated based on the Healthcare Cost and Utilization Project database and inflated to 2020 US dollars.. Per-patient all-cause grade 3/4 AE costs for nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib were $2703 vs. $4508 vs. $5772, and treatment-related grade 3/4 AE costs were $741 vs. $2722 vs. $4440 over ~12.8 months of FU. For nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib, per-patient all-cause grade 3/4 AE costs were $3120 vs. $5800 vs. $9285, while treatment-related grade 3/4 AE costs were $863 vs. $3162 vs. $5030 over ~26.6 months of FU.. Patients with aRCC treated with first-line nivolumab-based therapies had lower grade 3/4 all-cause and treatment-related AE costs than pembrolizumab-based therapies, suggesting a more favorable cost-benefit profile.

Topics: Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Costs and Cost Analysis; Humans; Ipilimumab; Kidney Neoplasms; Nivolumab; Sunitinib

The treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making.. To assess the CE of guideline-recommended approved first- and second-line treatment regimens.. A comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network-recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk.. Life years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed.. In patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments.. Pembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments.. Because new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.

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

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980. In recent years, new systemic therapies for HCC have been approved and a critical assessment of the existing data is necessary to balance benefits and harms and inform the development of evidence-based guidelines.. The American Gastroenterological Association formed a multidisciplinary group consisting of a Technical Review Panel and a Guideline Panel. The Technical Review Panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of systemic therapies in patients with advanced-stage HCC. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations.. The Panel reviewed the evidence, summarized in the Technical Review, for the following medications approved by the US Food and Drug Administration for HCC: first-line therapies: bevacizumab+atezolizumab, sorafenib, and lenvatinib; second-line therapies: cabozantinib, pembrolizumab, ramucirumab, and regorafenib; and other agents: bevacizumab, nivolumab, and nivolumab+ipilimumab.. The Panel agreed on 11 recommendations focused on systemic therapy for HCC in patients who are not eligible for locoregional therapy or resection, those with metastatic disease and preserved liver function, those with poor liver function, and those on systemic therapy as adjuvant therapy.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Hepatectomy; Humans; Liver Neoplasms; Liver Transplantation; Phenylurea Compounds; Pyridines; Quinolines; Ramucirumab; Retreatment; Sorafenib

Topics: Anilides; Antineoplastic Agents; Carcinoma, Medullary; Drug Approval; Humans; Mutation; Phenylurea Compounds; Piperidines; Precision Medicine; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

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

Sorafenib and Regorafenib are the recommended first- and second-line therapies in patients with advanced hepatocellular carcinoma (HCC). Lenvatinib and Cabozantinib have shown non-inferior antitumoral activities compared with the corresponding recommended therapies. The clinical trials have established recommended doses for each treatment that lead different blood concentrations in patients for Sorafenib (10 µM), Regorafenib (1 µM), Lenvatinib (0.1 µM), and Cabozantinib (1 µM). However, very low response rates are observed in patients attributed to intrinsic resistances or upregulation of survival signaling. The aim of the study was the comparative dose-response analysis of the drugs (0-100 µM) in well-differentiated (HepG2, Hep3B, and Huh7), moderately (SNU423), and poorly (SNU449) differentiated liver cancer cells in 2D/3D cultures. Cells harbors wild-type p53 (HepG2), non-sense p53 mutation (Hep3B), inframe p53 gene deletion (SNU423), and p53 point mutation (Huh7 and SNU449). The administration of regular used in vitro dose (10 µM) in 3D and 2D cultures, as well as the dose-response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Lenvatinib and Cabozantinib were particularly effective in moderately to poorly differentiated cells with mutated or lacking p53 that have lower basal oxygen consumption rate (OCR), ATP, and maximal respiration capacity than observed in differentiated HCC cells. Sorafenib and Regorafenib downregulated, and Lenvatinib and Cabozantinib upregulated epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor receptor (c-Met) in HepG2 cells. Conclusions: Sorafenib and Regorafenib were especially active in well-differentiated cells, with wild-type p53 and increased mitochondrial respiration. By contrast, Lenvatinib and Cabozantinib appeared more effective in moderately to poorly differentiated cells with mutated p53 and low mitochondrial respiration. The development of strategies that allow us to deliver increased doses in tumors might potentially enhance the effectiveness of the treatments.

Topics: Adult; Anilides; Apoptosis; Cell Culture Techniques; Cell Differentiation; Cell Proliferation; Cell Respiration; Female; Hep G2 Cells; Hepatocytes; Humans; Liver Neoplasms; Male; Mitochondria; Oxygen Consumption; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Sorafenib; Spheroids, Cellular; Tumor Suppressor Protein p53

Hepatocellular carcinoma (HCC) is one of the most lethal cancers. After many years of stagnation, there are now several systemic treatments available for patients with HCC.. To analyse the feasibility and efficacy of sequential systemic treatments in patients with HCC in clinical practice.. In this multicentre study, patients who were treated with novel systemic therapies for HCC between 2014 and 2019 at two referral centres, Hannover Medical School, Germany, and Medical University of Vienna, Austria, were included.. Overall, 85 patients were included of which 76 patients (89.4%) received more than one and a maximum of five systemic treatment lines. The most common therapy sequence was sorafenib (n = 72; 84.7%) followed by regorafenib (n = 37; 48.7%), whereas 11 patients were initially treated with lenvatinib (12.9%). Other second-line treatments included pembrolizumab, nivolumab, cabozantinib and ramucirumab. Hepatic function deteriorated during sequential systemic treatment in 48.6% of the patients as defined by an increase in at least one Child-Pugh point. Median overall survival (mOS) from the start of first systemic treatment was 35 months for patients with sequential systemic treatment compared to 9 months for patients with one systemic treatment line (P < 0.001). Patients previously treated with surgical/locoregional therapies had a longer mOS compared to patients with initial systemic treatment (66 vs 25 months; P = 0.020).. Sequential systemic treatment is feasible and effective in selected patients with HCC in clinical practice. Our study underlines the critical importance of well-preserved liver function for successful administration of sequential systemic therapy.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib

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

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2-5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

Topics: Anilides; Antibodies, Monoclonal, Humanized; beta Catenin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Clinical Trials as Topic; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Mutation; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines

Vandetanib¸ lenvatinib, and cabozantinib are tyrosine kinase inhibitors (TKIs) targeting VEGFR subtypes 1 and 2, EGFR and the RET-tyrosine kinase, thus considered as multiple TKIs. These TKIs have already been approved for treating patients suffering from thyroid cancer and renal cell carcinoma. Ellipticine, a DNA-damaging drug, is another anticancer agent that is effective against certain tumors of the thyroid gland, ovarian carcinoma, breast cancer and osteolytic breast cancer metastasis. Its anticancer efficiency is dictated by its oxidation with cytochrome P450 (CYP) and peroxidase enzymes. A number of studies testing the effectiveness of individual anticancer drugs, the pharmacological efficiencies of which are affected by their metabolism, alone or in a combination with other cytostatics demonstrated that such combination can have both positive and negative effects on treatment regimen. The aim of this study was to study the effect of vandetanib, lenvatinib and cabozantinib on oxidation of ellipticine which dictates its pharmacological efficiency.. Ellipticine oxidation catalyzed by hepatic microsomes, recombinant CYP enzymes and peroxidases (horseradish peroxidase, lactoperoxidase and myeloperoxidase) and the effect of TKIs (vandetanib, lenvatinib and cabozantinib) on this oxidation were analyzed by HPLC used for separation of ellipticine metabolites and quantification of their amounts formed during oxidation.. The CYP enzymatic system oxidizes ellipticine up to five metabolites (9-hydroxy-, 12-hydroxy-, 13-hydroxy-, 7-hydroxyellipticine, and ellipticine N2- oxide), while peroxidases form predominantly ellipticine dimer. Ellipticine oxidation catalyzed by rat and human hepatic microsomes was inhibited by vandetanib and cabozantinib, but essentially no inhibition was caused by lenvatinib. Of individual CYP enzymes catalyzing oxidation of ellipticine, TKIs inhibited oxidation of ellipticine catalyzed by CYP2D6 > 2D1 > 2C9 > 3A1 > 3A4, the CYP enzymes participating in ellipticine oxidation to metabolites increasing the ellipticine anticancer efficiency. On the contrary, they have essentially no inhibition effect on ellipticine oxidation catalyzed by CYP1A1 and 1A2, which are the enzymes that predominantly detoxify this drug. All tested TKIs had essentially no effect on oxidation of ellipticine by used peroxidases.. The results found demonstrate that TKIs vandetanib, lenvatinib and cabozantinib cause a decrease in oxidative activation of DNA-damaging drug ellipticine by several CYP enzymes in vitro which might lead to a decrease in its pharmacological efficiency. In contrast, they practically do not influence its detoxification catalyzed by CYP1A1, 1A2 and peroxidases. The present study indicates that tested TKIs seem not to have a potency to increase ellipticine anticancer efficiency.

Topics: Anilides; Animals; Cytochrome P-450 Enzyme Inhibitors; Ellipticines; Humans; Microsomes, Liver; Oxidation-Reduction; Peroxidases; Phenylurea Compounds; Piperidines; Pyridines; Quinazolines; Quinolines; Rats

In the past decade, targeted therapy with antiangiogenic drugs has become standard of care for most types of metastatic, progressive thyroid cancer. While these drugs were thought initially to be less toxic than traditional chemotherapy, they can have rare but serious and fatal toxicities. Once such toxicity that has been reported in other tumor types is upper airway fistula formation, which can be life-threatening.. Here, we describe three patients treated with antiangiogenic tyrosine kinase inhibitors at two academic institutions who developed aerodigestive fistula. All three patients had risk factors for fistula formation, which included external beam radiation and/or large tumor with invasion of the tracheal wall.. Fistula formation is a known but rare side effect of antiangiogenic tyrosine kinase inhibitors. Knowledge of the risk factors that may predispose thyroid cancer patients to this serious adverse event is vital prior to prescribing antiangiogenics. Particular caution should be observed when using these drugs in patients undergoing radiation therapy or surgery, or in patients whose tumor is invading vital structures of the neck, as they may be at higher risk of developing this rare complication. In these patients, antiangiogenic tyrosine kinase inhibitors should be used cautiously, patients should be aware of the risk, and physicians should monitor patients for symptoms of fistula.

Topics: Academic Medical Centers; Angiogenesis Inhibitors; Anilides; Combined Modality Therapy; Drugs, Investigational; Esophageal Fistula; Fatal Outcome; Humans; Indoles; Male; Middle Aged; Neck Dissection; Phenylurea Compounds; Postoperative Complications; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinolines; Receptor Protein-Tyrosine Kinases; Respiratory Tract Fistula; Risk Factors; Sunitinib; Texas; Thyroid Neoplasms; Thyroidectomy; Tracheoesophageal Fistula