Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Results of the randomized TORAVA phase II trial.

Abstract

4516 Background: Temsirolimus (T) and bevacizumab (B) have been approved for the treatment of mRCC. The T-B combination has proven feasible at full doses of each agent with promising activity in phase I. This study was aimed to promptly determine whether this combination could improve the results of available treatments. Methods: Untreated mRCC patients (pts) with ECOG PS £ 2 and measurable disease were randomized using a 2:1:1 ratio to T-B combination (arm A), sunitinib (arm B) or bevacizumab and a-interferon (arm C) in an open label, multicenter, non comparative phase II trial. Pts were treated until disease progression or unacceptable toxicity. The primary objective was to estimate the non-progression rate at 48 weeks (NPR-48) for arm A. Using Fleming's single-stage procedure and a NPR- 48 of 50% as the minimum needed for the combination to warrant further study, the planned sample size for arm A was 80 pts (assuming NPRs-48 of 35% in the pivotal trials [Motzer et al 2007, Escudier et al 2007]). Major secondary endpoints were toxicity, response rate (RR) and survival. Results: From 03/2008 to 05/2009, 171 pts were randomized: 88 (51%), 42 (25%) and 41 (24%) to arms A, B and C, respectively. Treatments were prematurely stopped for other reasons than progression in 43% (A), 12% (B) and 23% (C). Grade 3/4 events were observed in 36%, 14% and 27% pts in arms A, B, C respectively; two toxic deaths occurred in arm A. In an intent-to-treat analysis with a median follow-up of 43 weeks, NPRs-48 were 43.2% (95% CI, 32.7-54.2), 47.6% (95% CI, 32.0-63.6) and 65.9% (95% CI, 49.4-79.9) in arms A, B and C respectively. Best RRs (RECIST) were 25%, 24% and 34% respectively. Conclusions: The toxicity profile of the T-B combination was higher than expected, leading to a high drop-out rate. The results do not suggest any evidence of a synergistic/additive efficacy of this combination. Patients continue to be followed and updated data will be reported. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO, Bayer, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth Bayer, GlaxoSmithKline, Novartis, Pfizer, Wyeth GlaxoSmithKline, Roche, Wyeth