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; = 0.051), but the nominal significance level ( = 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. 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. 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, = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64–1.14, = 0.3) 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

中文翻译：

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依维莫司辅助治疗完全切除的透明细胞组织学极高风险肾细胞癌患者：3 期安慰剂对照 SWOG S0931 (EVEREST) 试验结果


EVEREST 是一项 3 期试验，受试者为肾切除术后复发风险为中高或极高的肾细胞癌 (RCC) 患者，随机接受依维莫司辅助治疗或安慰剂治疗。依维莫司观察到更长的无复发生存期 (RFS)（风险比 [HR] 0.85，95% 置信区间 [CI] 0.72–1.00；= 0.051），但未达到名义显着性水平（= 0.044）。为了将这些结果与辅助舒尼替尼和派姆单抗的积极 3 期试验结合起来，我们对具有极高风险疾病和透明细胞组织学的类似 EVEREST 患者群体进行了二次分析。确定具有任何透明细胞成分和极高风险疾病的肾切除术后患者，定义为 pT3a（3-4 级）、pT3b-c（任何级别）、T4（任何级别）或淋巴结阳性状态（N+）。使用按体能状态分层的 Cox 回归模型来比较治疗组之间的 RFS 和总生存期 (OS)。在 1499 名患者中，717 名具有透明细胞组织学特征和极高风险疾病； 699 名患者符合资格标准，其中 348 名患者被随机分配至依维莫司组，351 名患者被随机分配至安慰剂组。两组患者的特征相似。依维莫司组中只有 163/348 (47%) 患者按计划完成了所有治疗，而安慰剂组中这一比例为 225/351 (64%)。辅助依维莫司导致 RFS 显着改善（HR 0.80；95%CI 0.65–0.99，= 0.041）。未发现生存获益的证据（HR 0.85；95%CI 0.64–1.14，= 0.3）在复发风险极高的透明细胞肾细胞癌患者中，与安慰剂相比，辅助依维莫司导致 RFS 显着改善，但导致 RFS 显着改善。由于不良事件导致的高停药率。 尽管 OS 的治疗 HR 与 RFS 结果一致，但未达到统计学显着性。重点关注风险分层工具和/或生物标志物，以尽量减少那些不太可能受益的毒性风险，这些信息可以帮助为高风险肾细胞癌的未来辅助试验的设计提供信息