RAD001 vs placebo in patients with metastatic renal cell carcinoma (RCC)after progression on VEGFr-TKI therapy: Results from a randomized, double-blind, multicenter Phase-III study
Authors: R. J. Motzer, B. Escudier, S. Oudard, C. Porta, T. E. Hutson, S. Bracarda, N. Hollaender, G. Urbanowitz, A. Kay, A. Ravaud
Journal: Journal of Clinical Oncology (2008)

LBA5026 Background: RAD001 (everolimus) is an oral inhibitor of mTOR, an intracellular kinase that regulates cell proliferation and angiogenesis. Antitumor activity has been shown in a single-arm Phase-2 trial in pretreated mRCC with continuous daily therapy (JCO 2007;25[18S]:261s Abs 5107). Methods: Pts with RCC with a clear-cell component progressing on or <6 months (mo) after VEGFr-TKI therapy (sorafenib, sunitinib, or both) were randomized 2:1 to RAD001 (10 mg/d po) or placebo, both with best supportive care. Patients were stratified by MSKCC risk criteria and prior VEGFr-TKI therapy (1 vs 2). Progression-free survival (PFS), documented using RECIST and assessed via blinded, independent review, was the primary endpoint. At progression, treatment was unblinded and pts on placebo offered open-label RAD001. Based on a sample size of 362 pts, the trial had 90% power to detect a 33% risk reduction (HR 0.67), with a median exponential PFS improvement from 3.0 to 4.5 mo (stratified log-rank test). Results of a planned interim analysis are presented - as these met prespecified criteria for a positive trial, the Independent Data Monitoring Committee stopped the study to allow remaining patients on placebo to receive RAD001. Results: From 9/06–10/07, 272 pts were randomized to RAD001 and 138 to placebo. Demographics were well balanced (pooled median age 60y) as was prior VEGFr-TKI therapy (sunitinib 71%, sorafenib 55%, sunitinib+sorafenib 26%). 191 PFS events (47% of 410 pts) were reported by central review: 101 (37%) and 90 pts (65%) on RAD001 and placebo, respectively. Most common AEs (all grades/grade 3–4) were stomatitis (RAD001 36/4%, placebo 7/0%), anemia (28/7% vs 15/5%), and asthenia (28/2% vs 20/4%). 10% of pts had AEs leading to discontinuation with RAD001 vs 4% with placebo whereas dose reductions were required by 4% vs <1%. 68 deaths were observed, and study follow-up is ongoing to assess the secondary endpoint of overall survival. Conclusion: RAD001 resulted in a statistically and clinically significant improvement in PFS over placebo with a favorable safety profile in pts with mRCC after progression on other targeted therapies. Population N HR (95% CI) p- value RAD001 Placebo Median PFS (mo) (95% CI) All (independent review) 410 0.30(0.22-0.40) <0.0001 4.0 (3.7-5.5) 1.9 (1.8- 1.9) All (investigator review) 410 0.31 (0.24-0.41) <0.0001 4.6 (3.9-5.5) 1.8 (1.8-1.9) Prognostic group: MSKCC risk (independent review) Favorable 118 0.35 (0.20-0.61) <0.0001 5.5 (3.8-5.9) 2.2 (1.9-3.5) Intermediate 231 0.25 (0.16-0.37) <0.0001 3.9 (3.5-5.5) 1.8 (1.8-1.9) Poor 61 0.39 (0.19-0.81) 0.009 3.6 (1.9-5.4) 1.9 (1.7-3.6) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Bayer, GlaxoSmithKline, Innate, Pfizer Oncology, Roche, Schering-Plough, Wyeth Novartis Antigenics, Bayer, Genentech\T BioOncology, Novartis, Onyx, Pfizer Oncology, Roche, Wyeth Bayer, Genentech\T BioOncology, GlaxoSmithKline, Novartis, Pfizer Oncology, Roche, Wyeth Bayer, Novartis, Pfizer Oncology