%0 Journal Article
%T Adjuvant Everolimus in Patients with Completely Resected, Very High-risk Renal Cell Carcinoma of Clear Cell Histology: Results from the Phase 3 Placebo-controlled SWOG S0931 (EVEREST) Trial.
%A Lara PN
%A Tangen C
%A Heath EI
%A Gulati S
%A Stein MN
%A Meng M
%A Alva AS
%A Pal SK
%A Puzanov I
%A Clark JI
%A Choueiri TK
%A Agarwal N
%A Uzzo R
%A Haas NB
%A Synold TW
%A Plets M
%A Vaishampayan UN
%A Shuch BM
%A Lerner S
%A Thompson IM
%A Ryan CW
%J Eur Urol
%V 86
%N 3
%D 2024 Sep 28
%M 38811313
%F 24.267
%R 10.1016/j.eururo.2024.05.012
%X <B>OBJECTIVE: </B>EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology.<BR><B>METHODS: </B>Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms.<BR><B>UNASSIGNED: </B>Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC.