lenvatinib and Kidney-Neoplasms

For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta-analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents.. The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta-analysis.. Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07-0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50-3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06-11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01-1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07-0.31) and axitinib (OR 5.43, 95% CI 3.26-9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09-2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14-7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo.. Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC.

Topics: Antineoplastic Agents; Bayes Theorem; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Network Meta-Analysis; Phenylurea Compounds; Sorafenib; Vascular Endothelial Growth Factor A

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

At present, the combination of immune checkpoint inhibitors (ICIs) or an ICI and a tyrosine kinase inhibitor (TKI) are the main treatment options as first-line therapy for metastatic renal cell cancer (mRCC). Among them, pembrolizumab plus lenvatinib was recently launched in Japanese clinical practice.. In this review, the efficacies and safety profiles of pembrolizumab plus lenvatinib for mRCC between Japanese and global populations are compared. In addition, lenvatinib is currently available for the treatment of not only mRCC but also of endometrial, thyroid, thymic, and hepatocellular cancers. We briefly summarized the characteristics of pembrolizumab plus lenvatinib or lenvatinib monotherapy for these malignancies. Finally, the characteristics of pembrolizumab plus lenvatinib for mRCC in the Japanese population are briefly elucidated.. In order to develop optimal personalized treatment for mRCC patients, it is necessary for physicians who treat mRCC patients to possess in-depth knowledge of not only the efficacy and safety profile of the respective therapies but also of the interpatient heterogeneities between Japanese and global populations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; East Asian People; Humans; Kidney Neoplasms

The purpose of this article is to review the pharmacology, safety, evidence for current use, and potential futures uses for combination therapy with pembrolizumab and lenvatinib.. A literature review was carried out through PubMed to identify ongoing trials evaluating use, efficacy, and safety of combination pembrolizumab and lenvatinib. NCCN guidelines were utilized to identify current approved uses in therapy and medication package inserts were used to identify pharmacology and preparation requirements.. A total of five completed clinical trials and two ongoing trials were evaluated for use and safety of pembrolizumab with lenvatinib. Data suggests that combination therapy with pembrolizumab and lenvatinib can be used first line for clear cell renal carcinoma in patients with favorable risk or intermediate/poor risk and in endometrial carcinoma as a preferred second-line regimen for recurrent or metastatic disease for biomarker-directed systemic therapy in non-MSI-H/non-dMMR tumors. This combination may have potential for use in unresectable hepatocellular carcinoma and gastric cancer.. Use of non-chemotherapy containing regimens spare patients from extended durations of myelosuppression and reduce the risk of infection. Additionally, pembrolizumab with lenvatinib demonstrates efficacy as first line treatment in clear cell renal carcinoma, second line in endometrial carcinoma, and several potential uses on the horizon.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Endometrial Neoplasms; Female; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has shown efficacy and manageable safety across multiple cancer types. The recommended starting doses for lenvatinib differ across cancer types and indications based on whether it is used as monotherapy or as combination therapy.. This review covers clinical trials that established the dosing paradigm and efficacy of lenvatinib and defined its adverse-event profile as a monotherapy; or in combination with the mTOR inhibitor, everolimus; or the anti-PD-1 antibody, pembrolizumab; and/or chemotherapy.. Lenvatinib has been established as standard-of-care either as a monotherapy or in combination with other anticancer agents for the treatment of radioiodine-refractory differentiated thyroid carcinoma, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma, and is being investigated further across several other tumor types. The dosing and adverse-event management strategies for lenvatinib have been developed through extensive clinical trial experience. Collectively, the data provide the rationale to start lenvatinib at the recommended doses and then interrupt or dose reduce as necessary to achieve required dose intensity for maximized patient benefit. The adverse-event profile of lenvatinib is consistent with that of other tyrosine kinase inhibitors, and clinicians are encouraged to review and adopt relevant symptom-management strategies.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Iodine Radioisotopes; Kidney Neoplasms; Liver Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

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

Lenvatinib is a type I tyrosine kinase inhibitor exhibiting powerful antiangiogenic activity in cancer therapy. Displaying activity in multiple solid tumors, it has been approved in differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma as single agent or in combination. In addition, lenvatinib has shown promise in several other tumor types including medullary, anaplastic thyroid, adenoid cystic, and endometrial cancer. Exploring synergy between angiogenic and immune checkpoint inhibitors, the lenvatinib/pembrolizumab combination is poised to become the next pair of active drugs in endometrial, lung, and gastrointestinal malignancies. Despite robust activity, the drug can be difficult to tolerate. Optimization of dose and biomarkers for prediction of efficacy and toxicities will be of great help. IMPLICATIONS FOR PRACTICE: Readers will be presented with an update on U.S. Food and Drug Administration approval of lenvatinib and suggestions for off-label use in thyroid cancer and adenoid cystic carcinomas. They will become familiarized with the common side effects, frequency, and predicators of response. In addition, they will learn that different strengths of lenvatinib are prescribed and why. Finally, readers are pointed to the latest efforts to combine lenvatinib and pembrolizumab, as well as to unresolved issues such as long-term side effects/toxicities of this drug.

Topics: Humans; Kidney Neoplasms; Liver Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

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

This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.

Topics: Axitinib; Carcinoma, Renal Cell; Humans; Hypertension; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Sorafenib; Sunitinib

In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC).. Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed.. Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0.. Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Neoplasm Staging; Phenylurea Compounds; Quinolines; Treatment Outcome

To date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway. The association of these two drugs was demonstrated to enhance the inhibitory activity against VEGF and FGF-induced angiogenesis by a vertical inhibition of angiogenic signaling pathways, suggesting a synergistic activity. Areas covered: In this review we summarize the lenvatinib pharmacokinetics, pharmacodynamics, characteristics and the main clinical trial that showed lenvatinib activity in advanced RCC. Expert opinion: Lenvatinib plus everolimus showed promising results in a phase II trial, leading to FDA approval of this combination. Their synergic action on inhibiting the VEGF/VEGFR, FGF (a compensatory mechanism to VEGFR inhibition) and mTOR pathway could be a potential mechanism to overcome treatment resistance. Given that the activity of lenvatinib as an immune-regulator in tumor microenvironment has been demonstrated in cell lines, novel combinations, in particular with immune-checkpoint inhibitors, are under development.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Synergism; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Renal cell carcinoma (RCC) accounts for 2-3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC.. Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma.. Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Vascular Endothelial Growth Factor A

Sequential administration of single targeted agents has evolved as the dominant paradigm in advanced RCC treatment. Lenvatinib plus everolimus is the first combination therapy in advanced RCC to show improvement in efficacy compared to monotherapy in advanced RCC while maintaining manageable toxicity profile. Areas covered: This review gives a brief overview of the contemporary clinical data on lenvatinib including its mechanism of action, pharmacokinetics, efficacy and safety profile in combination with everolimus. The clinical applications of lenvatinib in combination with everolimus are addressed within the context of the current competitive therapeutic landscape of RCC. Expert commentary: Lenvatinib is a new VEGF receptor-targeted tyrosine kinase inhibitor approved in combination with everolimus for second-line therapy in patients with advanced renal cell carcinoma progressing on a first-line VEGF receptor-targeted tyrosine kinase inhibitor. The combination of lenvatinib with everolimus significantly improved progression-free survival compared with everolimus with a hazard ratio of 0.40 and increased objective response to 43%. Optimal sequence of therapy targeting the tumor and the immune system remains a challenge and further investigation is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Receptors, Vascular Endothelial Growth Factor

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Phenylurea Compounds; Quinolines; Treatment Outcome

Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Hypertension; Kidney Neoplasms; Neoplasm Metastasis; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; TOR Serine-Threonine Kinases

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

There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Dose-Response Relationship, Drug; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Survival Rate

In patients with mRCC options for second line therapies, following progression on anti-angiogenic agents, that demonstrate a survival advantage in clinical trials have been limited. Recently a number of agents have demonstrated efficacy in this setting. Here in we profile one such therapy, the combination of lenvatinib and everolimus, and discuss the expanded options for therapy available in this setting. Areas covered: In this review, we discuss current algorithms for treatment of mRCC in both the first-line and second-line setting. We discuss the recent addition of cabozantinib and nivolumab, in the second line setting, to the market. Lenvatinib's pharmacology, clinical efficacy and toxicity profile is discussed. A comprehensive literature review was performed using PUBMED. Expert commentary: The current treatment algorithms for mRCC will likely see significant change in the coming years. The addition of immunotherapy to our treatment options in mRCC is of particular importance. Future trials examining the use of immunotherapy, both as monotherapy and in combination with VEGF targeted therapy, will likely be a dominant influence in the therapeutic landscape of mRCC. Progress in terms of the rapid expansion of available active therapies in mRCC needs to be balanced with current deficiencies in terms of predictive biomarkers.

Topics: Algorithms; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease Progression; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Despite advances in metastatic renal cell carcinoma (mRCC) treatments, patients eventually progress and develop resistance to therapies targeting a single pathway. Lenvatinib inhibits VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT proto-oncogenes. In a randomized, Phase II trial evaluating patients with mRCC who had progressed after one prior VEGF-targeted therapy, progression-free survival was significantly improved with lenvatinib alone or in combination with everolimus versus everolimus alone. This review summarizes the clinical development of lenvatinib in mRCC, and how simultaneous targeting of multiple pathways involved in carcinogenesis and/or therapeutic resistance may improve patient outcomes. Lenvatinib plus everolimus may be a promising second-line treatment in patients with mRCC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease-Free Survival; Everolimus; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Treatment Outcome

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

Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560).. HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method.. Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales.. Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Quality of Life; Vascular Endothelial Growth Factor A

The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression-free survival and overall survival, in patients with previously untreated advanced renal cell carcinoma. This subset analysis investigated efficacy and safety in Japanese patients randomized to lenvatinib plus pembrolizumab or sunitinib in the CLEAR study.. Progression-free survival, overall survival, tumor response, and safety were assessed in Japanese patients with previously untreated advanced renal cell carcinoma randomized to receive lenvatinib plus pembrolizumab (n = 42) or sunitinib (n = 31). Efficacy outcomes were analyzed by independent imaging review per Response Evaluation Criteria in Solid Tumors, version 1.1.. Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 22.1 vs. 10.9 months; hazard ratio, 0.39; 95% CI, 0.20-0.74). Median overall survival was not estimable in the lenvatinib plus pembrolizumab arm and 30.6 months in the sunitinib arm (HR, 1.20; 95% CI, 0.39-3.66). Overall survival adjusted for the imbalance of Memorial Sloan-Kettering Cancer Center prognostic risk group favored lenvatinib plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.18-2.39). Objective response rate (69.0% vs. 45.2%; odds ratio, 2.71; 95% CI, 1.03-7.10) was higher and median duration of response (20.3 vs. 9.1 months) was longer with lenvatinib plus pembrolizumab versus sunitinib. Grade ≥ 3 treatment-emergent adverse events occurred in 95.2% versus 87.1% of patients in the lenvatinib plus pembrolizumab versus sunitinib arms.. These findings support lenvatinib plus pembrolizumab as a potential first-line treatment for Japanese patients with advanced renal cell carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; East Asian People; Humans; Kidney Neoplasms; Sunitinib

The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival.. To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups.. CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC.. Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment.. Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1.. Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified.. Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS.. In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a "complete response" or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

Topics: Carcinoma, Renal Cell; Disease Progression; Humans; Kidney Neoplasms; Sunitinib

In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up.. This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861.. Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93]).. Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma.. Eisai and Merck Sharp & Dohme.

Topics: Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Male; Middle Aged; Sunitinib

In the CLEAR trial, lenvatinib plus pembrolizumab met study endpoints of superiority vs sunitinib in the first-line treatment of patients with advanced renal cell carcinoma. We report the efficacy and safety results of the East Asian subset (ie, patients in Japan and the Republic of Korea) from the CLEAR trial. Of 1069 patients randomly assigned to receive either lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib, 213 (20.0%) were from East Asia. Baseline characteristics of patients in the East Asian subset were generally comparable with those of the global trial population. In the East Asian subset, progression-free survival was considerably longer with lenvatinib plus pembrolizumab vs sunitinib (median 22.1 vs 11.1 months; HR 0.38; 95% CI: 0.23-0.62). The HR for overall survival comparing lenvatinib plus pembrolizumab vs sunitinib was 0.71; 95% CI: 0.30-1.71. The objective response rate was higher with lenvatinib plus pembrolizumab vs sunitinib (65.3% vs 49.2%; odds ratio 2.14; 95% CI: 1.07-4.28). Dose reductions due to treatment-emergent adverse events (TEAEs) commonly associated with tyrosine kinase inhibitors occurred more frequently than in the global population. Hand-foot syndrome was the most frequent any-grade TEAE with lenvatinib plus pembrolizumab (66.7%) and sunitinib (57.8%), a higher incidence compared to the global population (28.7% and 37.4%, respectively). The most common grade 3 to 5 TEAEs were hypertension with lenvatinib plus pembrolizumab (20%) and decreased platelet count with sunitinib (21.9%). Efficacy and safety for patients in the East Asian subset were generally similar to those of the global population, except as noted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; East Asian People; Humans; Kidney Neoplasms; Sunitinib

Lenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies.. To assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus.. A randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor-targeted therapy (prior anti-programmed death-1/programmed death ligand-1 therapy permitted).. Patients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle.. The primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORR. The ORR. The study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC.. In this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Vascular Endothelial Growth Factor A

Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors.. Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed.. Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3-77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1.. This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified.. Clinical Trials.gov number: NCT03006887.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Transitional Cell; Feasibility Studies; Humans; Japan; Kidney Neoplasms; Lung Neoplasms

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

No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.. Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0).. PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).. The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.. The clinical trial registration number is NCT01136733.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Treatment Outcome

Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.. In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.. A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.. Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Sunitinib; Survival Analysis

Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy.. To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC.. This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease.. Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily.. The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method.. The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design.. Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination.. We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects.. This trial is registered at ClinicalTrials.Gov as NCT02915783.

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1-based combination therapy. IMPLICATIONS: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Follow-Up Studies; Genetic Variation; HLA Antigens; Humans; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Survival Rate

Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients.. We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants.. Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia).. Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC.. Eisai and Merck Sharp & Dohme.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Europe; Female; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Time Factors; Treatment Outcome; United States

Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.. Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORR. Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cohort Studies; Endometrial Neoplasms; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasms; Phenylurea Compounds; Quinolines

Lenvatinib plus everolimus is approved for the treatment of advanced renal cell carcinoma (RCC) after one prior vascular endothelial growth factor-targeted therapy. Lenvatinib plus pembrolizumab demonstrated promising antitumor activity in a Phase I/II trial of RCC.. We describe the rationale and design of the CLEAR study, a three-arm Phase III trial comparing lenvatinib plus everolimus and lenvatinib plus pembrolizumab versus sunitinib monotherapy for first-line treatment of RCC. Eligible patients must have advanced clear cell RCC and must not have received any prior systemic anticancer therapy. The primary end point is progression-free survival; secondary end points include objective response rate, overall survival, safety, health-related quality of life and pharmacokinetics. Biomarker evaluations are included as exploratory end points.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Everolimus; Female; Humans; Kidney Neoplasms; Male; Multicenter Studies as Topic; Phenylurea Compounds; Progression-Free Survival; Quality of Life; Quinolines; Randomized Controlled Trials as Topic; Sunitinib; Survival Analysis; Young Adult

To assess the tolerability, safety, pharmacokinetics and antitumor activities of lenvatinib, an oral inhibitor of multiple receptor tyrosine kinases, in combination with everolimus, an inhibitor of mammalian target of rapamycin, in Japanese patients with advanced or metastatic renal cell carcinoma after disease progression with vascular endothelial growth factor-targeted therapy.. Lenvatinib 18 mg and everolimus 5 mg once daily were administered on 28-day continuous cycles until disease progression or unacceptable toxicity. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03, and tumor response was assessed according to the Response Evaluation Criteria in Solid Tumor version 1.1. Pharmacokinetics sampling was carried out during the first cycle.. Seven patients with clear cell renal cell carcinoma received this combination treatment. Dose-limiting toxicity was not observed. The most commonly observed adverse events were thrombocytopenia and decreased appetite (100%), followed by hypertriglyceridaemia and palmar-plantar erythrodysesthesia syndrome (86%). The most common grade 3 adverse event was lymphopenia (43%). No grade 4 or 5 adverse events occurred. The steady-state mean areas under the concentration-time curves of lenvatinib and everolimus were 3220 and 401 ng·h/mL, respectively. Five patients (71%) had partial response, and one (14%) had stable disease.. Lenvatinib 18 mg and everolimus 5 mg once daily are well tolerated and manageable, and their combined administration has no significant effect on either drug's pharmacokinetics. Overall, this combination therapy shows encouraging antitumor activity in Japanese patients with renal cell carcinoma.

Topics: Aged; Carcinoma, Renal Cell; Drug Therapy, Combination; Everolimus; Female; Humans; Japan; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Phenylurea Compounds; Quinolines; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Phenylurea Compounds; Quinolines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Single-Blind Method; Tomography, X-Ray Computed

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Synergism; Everolimus; Humans; Kidney; Kidney Neoplasms; Neoplasm Metastasis; Phenylurea Compounds; Quinolines; Survival Analysis

Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma.. We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733.. Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib.. Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma.. Eisai Inc.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Quinolines

Lenvatinib is an oral multi-targeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT. Everolimus is an oral mammalian target of rapamycin inhibitor approved for advanced renal cell carcinoma (RCC). This phase 1b study assessed safety, maximum tolerated dose (MTD), and preliminary antitumor activity of lenvatinib plus everolimus in metastatic RCC (mRCC) patients.. Patients with advanced unresectable or mRCC and Eastern Cooperative Oncology Group performance status 0-1 were eligible (number of prior treatments not restricted). Starting dose was lenvatinib 12 mg once daily with everolimus 5 mg once daily administered continuously in 28-day cycles using a conventional 3 + 3 dose-escalation design. At the MTD, additional patients were enrolled in an expansion cohort.. Twenty patients (mean 58.4 years) received lenvatinib [12 mg (n = 7); 18 mg (n = 11); 24 mg (n = 2)] plus everolimus 5 mg. MTD was established as once daily lenvatinib 18 mg plus everolimus 5 mg. The most common treatment-related treatment-emergent adverse events (all dosing cohorts) were fatigue 60 % (Grade ≥3: 10 %), mucosal inflammation 50 %, proteinuria (Grade ≥3: 15 %), diarrhea (Grade ≥3: 10 %), vomiting (Grade ≥3: 5 %), hypertension, and nausea, each 40 %. In MTD and lowest-dose cohorts (n = 18), best responses of partial response and stable disease were achieved in 6 (33 %) and 9 (50 %) patients, respectively.. Lenvatinib 18 mg combined with everolimus 5 mg was associated with manageable toxicity consistent with individual agents and no new safety signals. Observed activity warrants further evaluation of the combination in advanced RCC patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Phenylurea Compounds; Quinolines; Sirolimus

No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab (PEMBRO) and lenvatinib (LEN) + PEMBRO, against metastatic renal cell carcinoma. This study aims to highlight the comprehensive differences in AEs between these two therapies based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In total, 28 937 records were extracted from the FAERS database, and 139 AEs grouped into the System Organ Class according to the Medical Dictionary for Regulatory Activities were analysed. Logistic regression analyses were performed, and the reporting odds ratio with a 95% confidence interval was determined. We found that the incidences of cardiac and hepatobiliary disorders for AXI + PEMBRO, and blood and lymphatic system, metabolism and nutrition, and vascular disorders for LEN + PEMBRO, all of which were associated with serious AEs, were higher than those for LEN + PEMBRO and AXI + PEMBRO, respectively. The differences in the AEs between AXI + PEMBRO and LEN + PEMBRO were not derived merely from those between AXI and LEN monotherapies. Furthermore, remarkable AE potentiation was observed for AXI + PEMBRO. As FAERS is a spontaneous reporting system comprising partially limited information, analysing more detailed relationships between AEs and patient or treatment characteristics was challenging in this study. The present study is the first to show the overall real-world postmarketing differences in AEs between AXI + PEMBRO and LEN + PEMBRO. Our novel findings will substantially improve clinical practice; we recommend comparing patients' conditions associated with the above AEs when selecting between these two therapies. PATIENT SUMMARY: Herein, we highlight the differences in adverse events (AEs) between axitinib + pembrolizumab and lenvatinib + pembrolizumab therapies using data from the real-world Food and Drug Administration Adverse Event Reporting System database aimed at patients with metastatic renal cell carcinoma. We identified AEs that needed attention in each combination. We recommend the differences in AEs to be considered when selecting these two therapies.

Topics: Adverse Drug Reaction Reporting Systems; Axitinib; Carcinoma, Renal Cell; Drug-Related Side Effects and Adverse Reactions; Humans; Kidney Neoplasms; Pharmacovigilance; United States; United States Food and Drug Administration

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 CLEAR trial indicated that survival benefits were generated with lenvatinib plus pembrolizumab (LP) or everolimus (LE) than with sunitinib for advanced renal cell carcinoma (aRCC). However, the high cost of immuno-target and dual-targeted treatment, we assessed the cost-effectiveness of lenvatinib plus pembrolizumab or everolimus in the first-line setting for treatment of patients with aRCC from the United States (US) payers' perspective.. A comprehensive Markov model was developed to evaluate the cost and effectiveness of LP or LE in first-line therapy for aRCC. We estimated life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Utility values and direct costs related to the treatments were gathered from the published studies. Then, one-way and probabilistic sensitivity analyses were performed. Additional subgroup analyses were considered.. Treatment with LP and LE provided an additional 0.67 QALYs (0.62 LYs) and 0.66 QALYs (0.90 LYs) compared with sunitinib, resulting in ICER of $131,656 per QALY and 201,928 per QALY, respectively. The most influential factor in this model was the cost of pembrolizumab with LP. Probabilistic sensitivity analysis showed there was a 58.97% and 28.91% probability that LP and LE were cost-effective at WTP values of $150,000 per QALY in the US. Subgroup analyses demonstrated that LP was more cost-effective for patients from Western Europe and North America, intermediate risk of the International risk group of Metastatic Renal Cell Carcinoma Database Consortium (IMDC), favorable and intermediate risk group of Memorial Sloan Kettering Cancer Center (MSKCC) and PD-L1 combined positive score greater than or equal to 1%.. From the perspective of the US payer, LP is a cost-effective option as first-line treatment for patients with aRCC at a WTP threshold of $150,000 per QALY, but LE is the opposite.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cost-Benefit Analysis; Cost-Effectiveness Analysis; Everolimus; Humans; Kidney Neoplasms; Sunitinib; United States

Several new treatment combinations have been approved in metastatic renal cell carcinoma (mRCC). To determine the optimal therapy on the basis of cost and health outcomes, we performed a cost-effectiveness analysis of approved immunotherapy-tyrosine kinase inhibitor/immunotherapy drug combinations and sunitinib using public payer acquisition costs in the United States.. We constructed a decision model with a 10-year time horizon. The seven treatment drug strategies included atezolizumab + bevacizumab, avelumab + axitinib, pembrolizumab + axitinib, nivolumab + ipilimumab (NI), nivolumab + cabozantinib, lenvatinib + pembrolizumab, and sunitinib. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values on the basis of the published literature. Costs included drug acquisition costs and costs for management of grade 3-4 drug-related adverse events. We used a partitioned survival model in which patients with mRCC transitioned between three health states (progression-free, progressive disease, and death) at monthly intervals on the basis of parametric survival function estimated from published survival curves. To determine cost-effectiveness, we constructed incremental cost-effectiveness ratios (ICERs) by dividing the difference in cost by the difference in effectiveness between nondominated treatments.. The least expensive treatment was sunitinib ($357,948 US dollars [USD]-$656,100 USD), whereas the most expensive was either lenvatinib + pembrolizumab or pembrolizumab + axitinib ($959,302 USD-$1,403,671 USD). NI yielded the most QALYs (3.6), whereas avelumab + axitinib yielded the least (2.5). NI had an incremental ICER of $297,465 USD-$348,516 USD compared with sunitinib. In sensitivity analyses, this ICER fell below $150,000 USD/QALY if the initial 4-month cost of NI decreased by 22%-38%.. NI was the most effective combination for mRCC, but at a willingness-to-pay threshold of $150,000 USD/QALY, sunitinib was the most cost-effective approach.

Topics: Axitinib; Carcinoma, Renal Cell; Cost-Effectiveness Analysis; Humans; Immunotherapy; Kidney Neoplasms; Nivolumab; Sunitinib; United States

Anti-PD-1 immunotherapy has been extensively used in treatment of patients with advanced metastatic renal cell carcinoma (mRCC). Several prospective clinical trials showed that the combined treatment of anti-PD-1 antibody plus lenvatinib, a potent receptor tyrosine kinase inhibitor (TKI), exhibited high response rate compared with single-agent sunitinib. However, whether the patients with primary resistance to PD-1 blockade could benefit from the addition of lenvatinib is still unclear. Herein, we reported a patient with mRCC who was primary resistant to pembrolizumab and achieved a durable complete response after a short-term treatment with lenvatinib. This case report indicates that the patients with primary resistance to anti-PD-1 therapy could benefit from the short-term lenvatinib in combination with anti-PD-1 therapy, and provides a useful paradigm worthy of establishing a clinical trial for mRCC patients with primary resistance to anti-PD-1 therapy.

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Phenylurea Compounds; Prospective Studies

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

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

Lenvatinib plus pembrolizumab showed significantly improved progression-free and overall survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma in the CLEAR study (NCT02811861). Here, we used CLEAR data to characterize common adverse reactions (ARs; adverse-event preferred terms grouped in accordance with regulatory authority review) associated with lenvatinib plus pembrolizumab and review management strategies for select ARs.. Safety data from the 352 patients who received lenvatinib plus pembrolizumab in the CLEAR study were analyzed. Key ARs were chosen based on frequency of occurrence (≥30%). Time to first onset and management strategies for key ARs were detailed.. The most frequent ARs were fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), and hypertension (56.3%); grade ≥3 severity ARs that occurred in ≥5% of patients were hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), weight decreased (8.0%), and proteinuria (7.7%). Median times to first onset of all key ARs were within approximately 5 months (approximately 20 weeks) of starting treatment. Strategies for effectively managing ARs included baseline monitoring, drug-dose modifications, and/or concomitant medications.. The safety profile of lenvatinib plus pembrolizumab was consistent with the known profile of each monotherapy; ARs were considered manageable with strategies including monitoring, dose modifications, and supportive medications. Proactive and prompt identification and management of ARs are important for patient safety and to support continued treatment.. NCT02811861.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Diarrhea; Fatigue; Humans; Hypertension; Kidney Neoplasms; Phenylurea Compounds

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).. HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.. VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.. By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.

Topics: Animals; Axitinib; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors

The treatment landscape of metastatic renal cell carcinoma (RCC) has significantly evolved in recent years with the advent and approval of multiple combinations of anti-angiogenic agents with immune checkpoint inhibitors, of which the combination of lenvatinib plus pembrolizumab is the most recent to be incorporated into clinical practice.. Herein, we provide an overview of the combination of lenvatinib plus pembrolizumab in metastatic RCC, including the mechanism of action, pharmacokinetics, efficacy, and safety profile.. Lenvatinib plus pembrolizumab has demonstrated substantial efficacy in patients with metastatic RCC in the first-line and refractory treatment setting with the highest reported results of radiological responses, complete responses, and progression free survival compared to all other RCC treatments. However, the field is currently still limited with the limited availability of biomarkers to inform on treatment selection and the lack of head-to-head studies across the effective RCC treatments. Ongoing and future studies are eagerly anticipated to uncover multiple unmet needs in RCC.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Tyrosine kinase inhibitors play an important role in the armamentarium against cancer. Lenvatinib is a multiple kinase inhibitor approved by the Food and Drugs Administration (FDA) for the treatment of advanced and radioresistant thyroid carcinomas and, in combination with everolimus, for renal cell carcinoma and unresectable hepatocellular carcinoma. The anti-tumoral activity is largely dependent on inhibition of neo-angiogenesis, and established side effects of anti-angiogenetic therapeutics include renal thrombotic microangiopathy (TMA). Here, we describe three cases of biopsy-proven renal TMA clinically presenting with proteinuria and stable serum creatinine in patients receiving lenvatinib for thyroid cancer. Microangiopathic lesions included glomerular basement membrane reduplication with segmental cellular interposition, mesangiolysis, and focal intracapillary and arteriolar thrombi. Drug-dose reduction or withdrawal was effective in renal function preservation, but cancer progressed in all patients. The management of lenvatinib-induced renal TMA remains a challenge. The best therapy in these patients is still uncertain. Earlier and more precise measurement of urine protein levels, allowing for early dose adjustment, could be effective in preventing further damage and drug discontinuation.

Topics: Carcinoma, Renal Cell; Humans; Kidney; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Thrombotic Microangiopathies

Topics: Antibodies, Monoclonal, Humanized; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

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

Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs.. We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used.. Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity.. Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs.. As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Vascular Endothelial Growth Factor A

Topics: Antibodies, Monoclonal, Humanized; Carcinoma, Renal Cell; Everolimus; Humans; Immunotherapy; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Few studies have evaluated real-world effectiveness of lenvatinib (Len)/everolimus (Eve) for advanced/metastatic renal cell carcinoma (a/mRCC). This study evaluated patient profiles and clinical outcomes of second- and subsequent-line (≥ 2L) Len/Eve for a/mRCC.. A longitudinal retrospective study examined adult patients initiating ≥ 2L Len/Eve for a/mRCC from May 13, 2016, to July 31, 2019. Len/Eve clinical trial participants or those treated for other primary tumors were excluded. Outcomes included objective response rate, duration of response, progression-free survival (PFS), time to treatment discontinuation, and overall survival. Time-to-event outcomes were estimated using Kaplan-Meier methods.. Seventy-nine patients were assessed: the median age was 64.8 years, 78.5% were Caucasian, 73.4% were male, 78.5% had an Eastern Cooperative Oncology Group performance status score of 0/1, 29.1% received 2L/3L Len/Eve, and the median number of prior lines of therapy was 3 (range, 1-8). At initial diagnosis, 55.7% had stage IV disease, 65.8% had International Metastatic risk scores of intermediate/poor, 19.0% favorable, and 15.2% with missing score. Thirty-one (39.2%) patients received immuno-oncology-based regimens, and 50.6% received tyrosine kinase inhibitors directly before Len/Eve initiation. The median time to treatment discontinuation was 5.7 months (95% CI, 3.3-6.9). The physician-assessed objective response rate was 55.7% (1.6% complete response and 54.1% with some degree of tumor shrinkage). The median duration of response was 9.7 months (95% CI, 5.8-17.1). The median PFS was 6.1 months (95% CI, 4.4-9.0). The median PFS for patients receiving Len/Eve post-immuno-oncology was 6.4 months (95% CI, 4.1-10.8) and for post-tyrosine kinase inhibitor 5.7 months (95% CI, 4.1-10.5). Median overall survival was 14.8 months (95% CI, 10.2-23.9).. In this longitudinal retrospective study, Len/Eve showed real-world effectiveness in clinical practice in a heavily pretreated a/mRCC patient population.

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Topics: Antibodies, Monoclonal, Humanized; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Lenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated.. The antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells targeted carbonic anhydrase IX (CAIX) in a murine renal cancer model.. The antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model.. Our study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.

Topics: Animals; Carbonic Anhydrase IX; CD8-Positive T-Lymphocytes; Chemokines; Female; Humans; Immunity, Cellular; Immunosuppressive Agents; Immunotherapy; Kidney Neoplasms; Mice, Nude; Myeloid-Derived Suppressor Cells; Neoplasms, Experimental; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptors, Chimeric Antigen; Tumor Microenvironment

Patients with primary refractory metastatic renal cell carcinoma (mRCC) have a dismal prognosis and poor response to subsequent treatments. While there are several approved second-line therapies, it remains critical to choose the most effective treatment regimen.. We identified 7 patients with clear cell mRCC who had primary resistance to vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor (ICI) combination therapy. The patients were treated with lenvatinib (a multitargeted TKI) plus everolimus (a mammalian target of rapamycin inhibitor). Among these 7 patients, 2 had prior TKI therapy, 3 had prior ICI therapy, and 2 had prior TKI and ICI therapy. We collected the patients' clinical characteristics, molecular profiles, treatment durations, and toxicity outcomes.. The median time to progression on prior therapies was 1.5 months. Lenvatinib plus everolimus was used either as a second-line (n = 4) or third-line (n = 3) therapy. As best responses, 3 patients had partial responses and 3 achieved stable disease. Patients were followed for ≥17 months; progression-free survival ranged from 3 to 15 months, and overall survival ranged from 4 to 17 months.. These 7 cases provide real-world data for the use of lenvatinib plus everolimus in patients with mRCC with primary resistance to first-line VEGF-targeted TKIs or ICI combination therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Everolimus; Female; Follow-Up Studies; Humans; Immunotherapy; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Quinolines; Sirolimus; Survival Rate

Papillary renal cell carcinoma (pRCC) represents the second most common histologic subtype of renal cell carcinoma and comprises 2 subtypes. Prognosis for type 2 is associated with poor clinical outcome. Current guidelines are based on phase II trials, phase III trials in patients with clear cell histology, or retrospective data.. To our knowledge, we describe for the first time a case of a patient with heavily pretreated metastatic pRCC who benefited from the combination of lenvatinib plus everolimus for more than 2 years.. According to immunohistologic and biological findings in our patient both on primary tumor and liver metastasis, we hypothesize that selected patients with metastatic pRCC, progressed to standard/available treatments (including angiogenic drugs, mTOR inhibitors, and immunotherapy) and dissociated response to everolimus, could benefit from adding lenvatinib to everolimus.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Male; Neoplasm Grading; Neoplasm Staging; Phenylurea Compounds; Quinolines; Retreatment; Tomography, X-Ray Computed; Treatment Outcome

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

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Fingers; Humans; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Quinolines; Skin Neoplasms; Tongue Neoplasms

The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, a mammalian target of rapamycin (mTOR) inhibitor, significantly improved clinical outcomes versus everolimus monotherapy in a phase II clinical study of metastatic renal cell carcinoma (RCC). We investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in three human RCC xenograft mouse models (A-498, Caki-1, and Caki-2). In particular, the combination led to tumor regression in the A-498 and Caki-1 models. In the A-498 model, everolimus showed antiproliferative activity, whereas lenvatinib showed anti-angiogenic effects. The anti-angiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki-1 xenografts, in which fibroblast growth factor (FGF)-driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in vascular endothelial growth factor (VEGF)-activated, and synergistic activity against FGF-activated endothelial cells, in cell proliferation and tube formation assays, as well as strongly suppressed mTOR-S6K-S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic KP-1 xenografts overexpressing VEGF or FGF. Our results indicated that simultaneous targeting of tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both VEGF and FGF signaling pathways by the combination underlies its superior anti-angiogenic activity in human RCC xenograft models.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Drug Synergism; Everolimus; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Humans; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Phenylurea Compounds; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; TOR Serine-Threonine Kinases; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

The FDA has approved the combination of lenvatinib and everolimus to treat advanced or metastatic renal cell carcinoma. The approval marks the first time that tyrosine kinase and mTOR inhibitors have been combined successfully as second-line treatment for renal cell carcinoma following prior VEGF-targeted therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Drug Approval; Everolimus; Humans; Kidney Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Treatment Outcome; United States; United States Food and Drug Administration