• Thomas E Hutson, M Dror Michaelson, Timothy M Kuzel, Neeraj Agarwal, Ana M Molina, James J Hsieh, Ulka N Vaishampayan, Ran Xie, Urmi Bapat, Weifei Ye, Rohit K Jain, and Mayer N Fishman.
• Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA. Electronic address: thomas.hutson@usoncology.com.
• Eur. Urol. 2021 Aug 1; 80 (2): 162-170.

BackgroundNon-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.ObjectiveTo determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC.Design, Setting, And ParticipantsThis open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease.InterventionLenvatinib (18 mg) plus everolimus (5 mg) orally once daily.Outcome Measurements And Statistical AnalysisThe 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.Results And LimitationsThe 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.ConclusionsLenvatinib 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.Patient SummaryWe 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.Clinical RegistrationThis trial is registered at ClinicalTrials.Gov as NCT02915783.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

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