Re: Efficacy of Everolimus in Advanced Renal Cell Carcinoma: A Double-Blind, Randomised, Placebo-Controlled Phase III Trial

Experts’ summary: This multi-institutional, double-blind, randomized, phase 3 study evaluated the efficacy of everolimus (RAD-001) as compared with placebo in patients with metastatic clear-cell renal cell carcinoma (RCC) who had progressed while on or within 6 mo of stopping vascular endothelial growth factor (VEGF)–targeted therapy (eg, sunitinib and/or sorafenib). The primary outcome of interest was progression-free survival, defined as the time from randomization to documented progression of disease or death, regardless of cause. Secondary end points of the study included overall survival, drug safety, objective tumor response rate based on measurable lesions, symptoms related to disease, and quality of life (QoL) evaluation. Overall, 272 and 138 patients were randomized to receive everolimus or placebo, respectively. An intention-to-treat analysis was used, and patients were stratified based on previous anti-VEGF therapy and Memorial Sloan-Kettering Cancer Center prognostic score. Although the study was designed to stop after 290 documented progression events, findings demonstrated a significant efficacy of everolimus over placebo at the second interim analysis; therefore, the study was discontinued after only 191 observed progression events. Patients receiving everolimus demonstrated both a decreased risk of progression (hazard ratio [HR]: 0.30; 95% confidence interval [CI]: 0.22–0.40) and increased median progression-free survival (4.0 versus 1.9 mo) compared with those receiving placebo, and this effect was seen across all subgroups. There was no significant difference in overall survival between the two groups, but this was likely due to a majority of the placebo arm crossing over to the everolimus group once disease progression had occurred. Although adverse events were more common in the everolimus group, no difference in health-related QoL was seen between the two arms.