EVEREST: Everolimus for renal cancer ensuing surgical therapy—A phase III study (SWOG S0931, NCT01120249).

Abstract

LBA4500 Background: Patients (pts) who undergo resection of renal cell carcinoma (RCC) with curative intent remain at risk for disease relapse. We conducted a phase III, double-blind, placebo (PB)-controlled, intergroup study to determine the effect of adjuvant treatment with the mTOR inhibitor everolimus (EVE) on recurrence-free survival (RFS). Methods: Pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to EVE 10 mg PO daily x 54 weeks or PB within 12 weeks of radical or partial nephrectomy. Randomization was stratified by risk group, histology (clear vs. non-clear cell), and performance status (0 vs. 1). RFS was the primary end point; secondary endpoints included overall survival (OS) and adverse events (AEs). The study was designed to detect an 18% reduction in the risk of RFS with EVE compared to PB, corresponding to an improvement of median RFS from 6.75 (based on E2805 ASSURE) to 8.23 years. Final analysis, using a stratified logrank test, was to occur after 804 total events or by 3/2022, whichever occurred first. Results: Between 4/2011 and 9/2016, 1545 pts were randomized to EVE (n = 775) or PB (n = 770). Overall pt characteristics included: intermediate high-/very high-risk 45%/55%; clear cell/non-clear cell 83%/17%. The DSMC recommended study continuation after each of 4 pre-specified interim analyses. 556 DFS events among 1499 eligible pts occurred by the time of final study analysis on 2/23/2022. The median follow-up was 76 months. RFS was improved with EVE vs. PB (HR 0.85, 95% CI, 0.72 – 1.00; P 1-sided = 0.0246), narrowly missing the pre-specified, one-sided significance level of 0.022 which accounted for interim analyses. Median RFS was not reached; the 6-year RFS estimate was 64% for EVE and 61% for PB. RFS improvement with EVE vs. PB was observed in the very high-risk group (HR 0.79, 95% 0.65-0.97; P 1-sided = 0.011) but not in the intermediate high-risk group (HR 0.99, 95% CI 0.73-1.35, P 1-sided = 0.48) ( P for interaction = 0.22). With 290 deaths, OS was similar between arms (HR 0.90, 95% CI, 0.71 – 1.13; P 1-sided = 0.178). Fewer pts completed all 54 weeks of study treatment in the EVE group (45% v 69%). In the EVE group, 37% withdrew due to AEs (vs 5% in PB). Grade 3-4 AEs occurred in 46% of pts treated with EVE and 11% with PB. The most common grade 3-4 AEs were mucositis (14% v 0%), hypertriglyceridemia (11% vs. 2%), and hyperglycemia (5% vs. 0%). Conclusions: Adjuvant EVE improved RFS in RCC pts after nephrectomy, but the nominal significance level was narrowly missed. The RFS improvement was seen despite a high rate of early treatment discontinuation. A 21% improvement in RFS with EVE was observed in pts with very high-risk disease, a group for whom adjuvant therapy may be most relevant. Clinical trial information: NCT01120249.