Phase 3 trial of everolimus for metastatic renal cell carcinoma

Abstract

for the RECORD-1 Study Group BACKGROUND: A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported. METHODS: Patients with mRCC (N ¼ 416) were randomized (2:1) to everolimus 10 mg/d (n ¼ 277) or placebo (n ¼ 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus. RESULTS: The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in !5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P ¼ .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01). CONCLUSIONS: These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib. Cancer 2010;116:4256-65.

New Perspectives on the Treatment of Metastatic Renal Cell Carcinoma: An Introduction and Historical Overview

“…In pivotal phase III trials, bevacizumab, sunitinib, sorafenib, pazopanib, and temsirolimus have shown clinical benefit for patients with treatment-naïve or cytokine-pretreated RCC by prolonging progression-free or overall survival (temsirolimus only) times [8 -15]. Clinical benefit was observed in patients with metastatic RCC treated with everolimus as a second-line therapy after failure of sunitinib or sorafenib, as demonstrated by the more than double median progression-free survival time, compared with placebo [16,17].…”

Vascular-targeted agents for the treatment of angiosarcoma

“…The VEGF gene, located at chromosome 6p12, consists of eight exons. mRNA splice variants involving exons 6 and 7 result in different VEGF isoforms, including VEGF 121 , VEGF 165 , VEGF 189. These isoforms have distinct matrix binding properties that modify their solubility and biological activity, of which VEGF 165 is the most abundant and biologically active [6].…”

“…Cleavage of VEGFA mRNA results in different VEGFA isoforms with distinct biological characteristics: VEGFA 121 , VEGFA 165 and VEGFA 189 . VEGFA 165 …”

“…mTOR inhibitors have demonstrated clinical benefit in the treatment of advanced renal cell carcinoma [189], and in a recent phase III study of maintenance ridaforolimus after chemotherapy for advanced soft tissue sarcoma, showed a small but statistically significant increase in progression free survival -angiosarcoma specific responses were unreported [190].…”

Beyond Traditional Outcomes: Improving Quality of Life in Patients with Renal Cell Carcinoma

“…HRQOL was evaluated with the EORTC QLQ-C30 and the FKSI-DRS before randomization, at day 1 of each cycle, and upon study discontinuation [25,34]. On the basis of an analysis of longitudinal mean scores on the EORTC QLQ-C30 and FKSI-DRS, HRQOL was sustained during everolimus therapy [25].…”