Abstract：
OBJECTIVE: 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.
METHODS: 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.
UNASSIGNED: 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.
METHODS: 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.
UNASSIGNED: 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.
摘要：
目的：EVEREST是一项针对肾细胞癌（RCC）患者的3期试验，这些患者在肾切除术后复发风险中等-高或极高，随机接受依维莫司辅助治疗或安慰剂治疗。使用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;p=0.051），但未达到名义显著性水平(p=0.044)。为了将这些结果与舒尼替尼和派姆单抗辅助治疗的阳性3期试验联系起来，我们在具有非常高危疾病和透明细胞组织学的类似EVEREST患者人群中进行了二次分析.
方法：具有任何透明细胞成分和非常高风险疾病的肾切除术后患者，定义为pT3a（3-4级），pT3b-c（任何等级），T4（任何等级），或节点正状态(N+)，已确定。使用按性能状态分层的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有透明细胞组织学和非常高风险的疾病;699符合资格标准，其中348人被随机分配到依维莫司手臂，和351到安慰剂组。两臂之间的患者特征相似。依维莫司组中只有163/348（47％）患者按计划完成了所有治疗，安慰剂组的225/351（64％）。依维莫司佐剂导致RFS的统计学显着改善（HR0.80;95CI0.65-0.99，p=0.041）。未发现生存获益的证据（HR0.85;95CI0.64-1.14，p=0.3）结论和临床意义：在复发风险非常高的透明细胞RCC患者中，与安慰剂相比,依维莫司佐剂导致RFS显著改善,但由于不良事件导致高停药率.尽管OS的治疗HR与RFS结果一致，没有达到统计学意义。重点关注风险分层工具和/或生物标志物，以最大程度地减少那些不太可能受益的人的毒性风险，这些信息有助于为高危肾细胞癌患者未来辅助试验的设计提供参考摘要:我们评估了在手术切除透明细胞肾癌后使用依维莫司与安慰剂相比的治疗复发风险非常高.我们发现，依维莫司治疗的患者的生存结果更好，尽管这些患者的副作用发生率较高。
方法：具有任何透明细胞成分和非常高风险疾病的肾切除术后患者，定义为pT3a（3-4级），pT3b-c（任何等级），T4（任何等级），或节点正状态(N+)，已确定。使用按性能状态分层的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有透明细胞组织学和非常高风险的疾病;699符合资格标准，其中348人被随机分配到依维莫司手臂，和351到安慰剂组。两臂之间的患者特征相似。依维莫司组中只有163/348（47％）患者按计划完成了所有治疗，安慰剂组的225/351（64％）。依维莫司佐剂导致RFS的统计学显着改善（HR0.80;95CI0.65-0.99，p=0.041）。未发现生存获益的证据（HR0.85;95CI0.64-1.14，p=0.3）结论和临床意义：在复发风险非常高的透明细胞RCC患者中，与安慰剂相比,依维莫司佐剂导致RFS显著改善,但由于不良事件导致高停药率.尽管OS的治疗HR与RFS结果一致，没有达到统计学意义。重点关注风险分层工具和/或生物标志物，以最大程度地减少那些不太可能受益的人的毒性风险，这些信息有助于为高危肾细胞癌患者未来辅助试验的设计提供参考摘要:我们评估了在手术切除透明细胞肾癌后使用依维莫司与安慰剂相比的治疗复发风险非常高.我们发现，依维莫司治疗的患者的生存结果更好，尽管这些患者的副作用发生率较高。
