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Clinical Trial
. 2024 Aug 1;7(8):e2425288.
doi: 10.1001/jamanetworkopen.2024.25288.

Adjuvant Everolimus in Non-Clear Cell Renal Cell Carcinoma: A Secondary Analysis of a Randomized Clinical Trial

Shuchi Gulati  1 , Catherine Tangen  2 , Christopher W Ryan  3 , Ulka N Vaishampayan  4 , Brian M Shuch  5 , Pedro C Barata  6 , Deepak K Pruthi  7 , Cristiane D Bergerot  8 , Abhishek Tripathi  9 , Seth P Lerner  10 , Ian M Thompson Jr  11 , Primo N Lara Jr  1 , Sumanta K Pal  9
Affiliations
Clinical Trial

Adjuvant Everolimus in Non-Clear Cell Renal Cell Carcinoma: A Secondary Analysis of a Randomized Clinical Trial

Shuchi Gulati et al. JAMA Netw Open. .

Abstract

Importance: Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant.

Objective: To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC.

Design, setting, and participants: This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022.

Intervention: The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo.

Main outcomes and measures: The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS.

Results: Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high-risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high-risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non-clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo.

Conclusions and relevance: In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out.

Trial registration: ClinicalTrials.gov Identifier: NCT01120249.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gulati reported receiving grants from ONCOC4 (paid to institution) and personal fees from EMD Serono, Aveo, Mashup Media, MJH LifeSciences, Medical Educators Consortium, Peer View, and ASCO outside the submitted work. Dr Ryan reported receiving grants from Ayala, Bristol Myers Squibb, Daiichi-Sankyo, Deciphera, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar Therapeutics, Pfizer, Xynomic, Rain Therapeutics, PTC Therapeutics, NiKang Therapeutics, Shasqi, PF Argentum IP Holdings, IO Biotech ApS, Seagen, Boehringer Ingelheim, and ALX Oncology outside the submitted work. Dr Vaishampayan reported receiving personal fees from Bristol Myers Squibb, Exelixis, Bayer, Pfizer, and Gilead and grants from Merck outside the submitted work. Dr Barata reported receiving grants from Exelixis, Janssen, and Arcus and personal fees from Bayer, Pfizer, Caris Life Sciences, UroToday, AstraZeneca, Myovant, Merck, Targeted Oncology, Bristol Myers Squibb, MJH Life Sciences, Seagen, Eisai, and Astellas outside the submitted work. Dr Tripathi reported receiving personal fees from Exelixis, Bayer, Seattle Genetics, Aadi Biosciences, and Deka Biosciences and grants from Aravive and EMD Serono outside the submitted work. Dr Lerner reported receiving grants from Aura Bioscience, Surge Therapeutics, FKD, and QED Pharmaceutical and personal fees from Ferring, UroGen, Incyte, Protara, Dava, UroToday, and Grand Rounds Urologyoutside the submitted work; in addition, Dr Lerner has a patent for The Cancer Genome Atlas classifier issued Tempus. Dr Pal reported receiving personal fees from CRISPR Therapeutics, MJH Associates, Intrinsiq, and Ipsen outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Kaplan-Meier Curves for Recurrence-Free Survival and Overall Survival in Patients with Papillary and Chromophobe Renal Cell Carcinoma (RCC)
See this image and copyright information in PMC

Comment in

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