Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.

• MeSH
• Quinolines * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Phenylurea Compounds * administration & dosage   therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   mortality   secondary   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sunitinib * administration & dosage   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria. MATERIALS AND METHODS: This retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 524 favorable-risk patients were included in the analysis. After a median follow-up of 37.2 months, the median OS in the overall population was 56.1 months. There was no significant difference in OS between patients receiving sunitinib and those receiving TKI + ICI combinations (p = 0.761). Patients on TKI + ICI had significantly longer PFS compared to patient treated with sunitinib (30.7 vs 22.9 months, p = 0.007). Analysis of OS and PFS based on metastatic site revealed that patients with bone metastases benefited more from ICI plus TKI (56 patients with bone metastases receiving IO + TKI, 38 received pembrolizumab plus axitinib, 15 cabozantinib plus nivolumab and 3 pembrolizumab plus lenvatinib), while sunitinib was more effective for pancreatic and glandular metastases. Additionally, the number of metastatic sites played a role, with TKI plus ICI showing superiority in patients with a single metastatic site. The time from RCC diagnosis to metastatic disease also impacted outcomes, with TKI plus ICI being more effective in patients with a shorter interval (i.e., < 36 months). CONCLUSIONS: The choice between upfront combination or monotherapy for metastatic favorable prognosis RCC remains a current issue. While combination therapy offers prolonged PFS, it does not necessarily translate to improve OS compared to sunitinib. This real-world study supports the superiority in terms of PFS of TKI plus ICI vs TKI monotherapy but not in OS. Probable, other clinical factors should be taking into account to make clinical treatment decisions in this setting.

• MeSH
• Quinolines therapeutic use   administration & dosage   MeSH
• Adult MeSH
• Phenylurea Compounds therapeutic use   administration & dosage   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   immunology   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   immunology   mortality   pathology   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Pyridines MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Sunitinib * therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

• MeSH
• Survival Analysis MeSH
• Quinolines * MeSH
• Phenylurea Compounds * MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• Carcinoma, Renal Cell * pathology   MeSH
• Humans MeSH
• Kidney Neoplasms * pathology   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Sunitinib adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

• Keywords
• kabozantinib,
• MeSH
• Antibodies, Monoclonal, Humanized pharmacology   therapeutic use   MeSH
• Tyrosine Kinase Inhibitors * pharmacology   classification   therapeutic use   MeSH
• Carcinoma, Renal Cell * diagnosis   drug therapy   secondary   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lung Neoplasms diagnostic imaging   drug therapy   secondary   MeSH
• Nivolumab pharmacology   therapeutic use   MeSH
• Sunitinib pharmacology   therapeutic use   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

• Keywords
• kabozantinib,
• MeSH
• Patient Compliance MeSH
• Tyrosine Kinase Inhibitors * administration & dosage   pharmacology   classification   therapeutic use   MeSH
• Carcinoma, Renal Cell * diagnosis   drug therapy   radiotherapy   secondary   MeSH
• Middle Aged MeSH
• Humans MeSH
• Spinal Neoplasms diagnostic imaging   drug therapy   secondary   MeSH
• Nivolumab pharmacology   therapeutic use   MeSH
• Tomography, X-Ray Computed methods   MeSH
• Disease Progression MeSH
• Sunitinib pharmacology   therapeutic use   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Ipilimumab administration & dosage   therapeutic use   MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   MeSH
• Nivolumab administration & dosage   therapeutic use   MeSH
• Randomized Controlled Trials as Topic MeSH
• Sunitinib administration & dosage   therapeutic use   MeSH
• Check Tag
• Humans MeSH

Renální karcinom (RCC) představuje přibližně 3 % všech zhoubných nádorů, v době diagnózy je 15 % nádorů v metastatickém stadiu. Po dlouhá léta bývala cytoredukční nefrektomie základem léčby. Pro pacienty s metastatickým onemocněním je cytoredukční nefrektomie (CN) převážně paliativním výkonem a je nezbytná systémová léčba. Adrenalektomie jako součást CN není považována za standardní součást výkonu s výjimkou evidentní invaze nádoru do nadledviny. Lymfadenektomie jako součást CN má pouze stagingový efekt. Výsledky analýz do doby cytokinů, porovnávajících CN plus imunoterapii založenou na interferonu vs. pouze imunoterapie interferonem, prokázaly lepší celkové přežití (overall survival – OS) u pacientů léčených CN. Možnosti léčby se však rychle rozšířily díky zavedení terapie cílené na molekulární mechanismy, které jsou základem karcinogeneze RCC. Z pohledu dnešní moderní onkologie je otázkou, u koho a kdy zařadit do léčby mRCC nefrektomii. Výsledky studií CARMENA a SURTIME prokázaly, že pacienti, kteří vyžadují systémovou léčbu, profitují z okamžité medikamentózní léčby. Samotná léčba sunitinibem není horší ve srovnání s okamžitou CN následovanou sunitinibem u pacientů se středním a nízkým rizikem MSKCC, kteří vyžadují systémovou léčbu. Předběžné výsledky studií ukazují, že kombinace IO + IO (IO – imunoterapie) nebo TKI + IO (TKI – inhibitory tyrosinové kinázy) mají lepší účinek na primární nádor a metastázy ve srovnání se samotným sunitinibem. Pacienti s ponechaným primárním nádorem léčení kombinovanou terapií na bázi IO mají lepší přežití bez známek progrese (PFS − progression-free survival) a OS v explorativních podskupinových analýzách ve srovnání s léčbou sunitinibem. U mRCC pacientů s klinickou odpovědí na kombinace založené na IO lze zvážit následnou CN. Cílem této práce je vymezit roli, současné postavení a načasování chirurgické léčby u metastatického onemocnění.

Renal cell carcinoma (RCC) accounts for approximately 3% of all malignant tumors, and 15% of tumors are metastatic at time of diagnosis. For many years, cytoreductive nephrectomy was the mainstay of treatment. For the patients with metastatic disease, cytoreductive nephrectomy (CN) is predominantly a palliative procedure and systemic therapy is essential. Adrenalectomy as a part of CN is not considered as a standard part of the procedure except for obvious tumor invasion into the adrenal gland. Lymfadenectomy as a part of CN has only staging effect. Results of cytokine study comparing CN plus interferon-based immunotherapy vs. interferon immunotherapy alone have shown improved overall survival (OS) in patients treated with CN. However, treatment options have rapidly expanded thanks to introduction of therapies targeting the molecular mechanisms underlying RCC carcinogenesis. From the point of view of today's modern oncology, the question is in whom and when to include nephrectomy in the treatment of mRCC. Results from the CARMENA and SURTIME studies have shown that patients who require systematic therapy benefit from immediate medical treatment. Sunitinib alone is non-inferior compared with immediate CN followed by sunitinib in patients with intermediate and low risk MSKCC who require systemic therapy. Exploratory results from the studies show that IO + IO (IO - immunotherapy) or TKI + IO (TKI - tyrosin kinase inhibitor) combination have better effect on primary tumor and metastasis in the comparison with sunitinib alone. Patients with retained primary tumor treated with IO-based combination therapy have better progression-free survival and OS in exploratory subgroup analyzes compared with sunitinib treatment. In mRCC patients with a clinical response to the combination based on IO subsequent CN can be considered. The aim of this study is to define the role, current status and timing of surgical treatment in metastatic disease.

• MeSH
• Molecular Targeted Therapy methods   MeSH
• Cytoreduction Surgical Procedures methods   MeSH
• Progression-Free Survival MeSH
• Immunotherapy methods   MeSH
• Tyrosine Kinase Inhibitors administration & dosage   therapeutic use   MeSH
• Carcinoma, Renal Cell * pathology   therapy   MeSH
• Clinical Studies as Topic MeSH
• Drug Therapy, Combination methods   MeSH
• Humans MeSH
• Kidney Neoplasms pathology   therapy   MeSH
• Nephrectomy methods   MeSH
• Antineoplastic Agents administration & dosage   pharmacology   therapeutic use   MeSH
• Sunitinib administration & dosage   therapeutic use   MeSH
• Check Tag
• Humans MeSH

Aim: To compare the efficacy of first-line immune checkpoint inhibitor (ICI)-based combinations in metastatic renal cell carcinoma (mRCC) patients stratified by chronological age. Methods: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, hazard ratios for overall survival (OS) from randomized controlled trials were synthesized. Results: Five RCTs were eligible for meta-analyses. ICI-based combinations significantly improved OS compared with sunitinib alone, both in younger (<65 years) and older (≥65 years) patients, whereas the OS benefit was significantly better in younger patients (p = 0.007). ICI-based combinations did not improve OS in patients aged ≥75 years. Treatment rankings showed age-related differential recommendations regarding improved OS. Conclusion: OS benefit from first-line ICI-based combinations was significantly greater in younger patients. Age-related differences could help enrich shared decision-making.

• MeSH
• Immunotherapy MeSH
• Immune Checkpoint Inhibitors MeSH
• Carcinoma, Renal Cell * therapy   MeSH
• Humans MeSH
• Kidney Neoplasms * therapy   MeSH
• Sunitinib MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Review MeSH

Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma.

• MeSH
• Axitinib adverse effects   MeSH
• Carcinoma, Renal Cell * pathology   MeSH
• Humans MeSH
• Kidney Neoplasms * pathology   MeSH
• Follow-Up Studies MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Sunitinib therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

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.

• MeSH
• Carcinoma, Renal Cell * drug therapy   ethnology   pathology   MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   ethnology   pathology   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Sunitinib therapeutic use   MeSH
• East Asian People MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Equivalence Trial MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH