Sorafenib In Advanced Renal Cell Carcinoma (RCC): Survival And Biomarker Results From A Phase III Trial
April 13, 2008
UroToday.com - Dr. Porta presented this talk on behalf of the sorafenib (Sor) TARGET clinical trial group. It is a follow-up on the significant progression-free survival (PFS) benefit for sorafenib (Sor) versus placebo (P) as seen in a large multicenter Phase III trial (TARGET) in patients (pts) with advanced RCC. In May 2007, P pts were allowed to cross over to Sor. In this report the investigators provide the final OS and biomarker data.
Final OS analysis was planned at ~540 events. To minimize effect of crossover on OS, a secondary analysis was planned censoring P data on June 30, 2007. Plasma VEGF (n=712 pts) and soluble VEGFR2 (sVEGFR2) [n=717] were measured by ELISA at baseline (BL), cycle 1 day 21 (C1D21), and cycle 3 day 1 (C3D1). Phospho-ERK was assessed by immunohistochemistry.
Pts (n=903) were randomized to Sor (n=451) or P (n=452). The analysis before crossover showed an estimated 39% OS improvement for Sor vs. P. An ITT analysis 6 months after crossover that included P pts (n=216) who had crossed to Sor showed a 30% improvement in OS for Sor vs. P. Pre-specified O’Brien Fleming statistical boundaries were not reached by these OS differences. Final OS at 561 deaths showed a non-significant improvement of 13.5% for Sor vs. P (median 17.8 vs. 15.2 months). A pre-planned secondary analysis censoring P data showed the confounding effect of crossover: a significant OS benefit for Sor vs. P was seen. Following Sor treatment, plasma VEGF levels increased by 32% (n=279) at C1D21 and by 47% (n=203) at C3D1. In contrast, plasma sVEGFR2 decreased by 18% (n=282) and by 24% (n=206) at C1D21 and C3D1, respectively. Using a COX proportional hazards model examining VEGF and MSKCC score in P pts, BL VEGF was an independent prognostic factor for PFS (p=0.014). VEGF was also prognostic for OS in a model including ECOG PS, MSKCC, and treatment group as variables in P and Sor pts (p=0.001). High BL VEGF levels were significantly associated with higher ECOG PS (p10mg/dL (p=0.0004). Pts with high BL VEGF (>131 pg/ml) had a relatively poor prognosis in the P arm while a trend toward a greater PFS benefit was observed in the Sor arm (Sor vs. P, HR=0.48 vs. 0.64 for high vs. low VEGF, p=0.096). Tumor DNA sequencing of the VHL exons from 68 pts showed that improved PFS in the Sor arm was independent of VHL mutational status (Sor vs. P, HR=0.52 vs. 0.49 for mutated VHL vs. wild-type VHL).
Presented by: C. Porta, MD, et al, at the European Association of Urology - 23rd Annual EAU Congress - March 26 - 29, 2008 - Milan, Italy
Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS
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