Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): Impact of crossover on survival

Abstract

4524 Background: Sorafenib was approved for advanced RCC in the USA December 2005. A Phase III randomized double-blind, placebo-controlled trial demonstrated an estimated 39% improvement in survival for patients receiving sorafenib versus placebo (HR= 0.72, p = 0.018) (ECCO 2005). These data supported independently reviewed doubling of PFS to 24 weeks in RCC patients receiving sorafenib compared with placebo (12 weeks) (p < 0.000001) (ASCO 2005). Based on the statistical significance and magnitude of PFS benefit, patients were unblinded and placebo patients allowed to crossover to sorafenib in April 2005. A prospectively planned interim OS analysis reflecting impact of crossover of placebo patients is presented. Methods: OS data up to November 30, 2005, were analyzed in this interim analysis using a stratified log-rank test comparing the two treatment groups. In order to examine the effect of crossover on OS, a secondary analysis was performed censoring data from patients randomized to placebo at June 30, 2005. Results: A total of 903 patients were randomized (451 to sorafenib, 452 to placebo) and >200 placebo patients crossed over to sorafenib. Baseline characteristics were similar between treatment arms. There were 367 deaths. The median OS was 19.3 months for sorafenib versus 15.9 months for placebo (HR = 0.77; 95% CI 0.63, 0.95; p = 0.015); although this did not attain the level of significance specified for the interim analysis (α = 0.009), a continued favorable trend in survival benefit was observed. With censoring of crossover data, the median OS was 19.3 months for sorafenib versus 14.3 months for placebo (HR = 0.74, 95% CI 0.58, 0.93; p = 0.010). Conclusion: Sorafenib is the first novel, oral approved treatment for advanced RCC in more than a decade. Previous information on the effect of crossover on OS in randomized oncology studies is limited. The lower HR observed after censoring placebo patients crossed over to sorafenib suggests a continued beneficial effect of sorafenib. Final results await more mature data. [Table: see text]