Originally published as JCO Early Release 10.1200/JCO.2008.19.5511 on May 18 2009

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Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial

From the From Institut Gustave Roussy, Villejuif; Hôpital Européen Georges Pompidou, Paris; Centre Léon Bérard, Lyon; Institut Claudius Regaud, Toulouse; Centre René Gauducheau, Saint-Herblain, France; Cambridge Research Institute, Cambridge; Royal Marsden Hospital, Surrey, United Kingdom; Military School of Medicine; Centrum Onkologii, Warsaw, Poland; Urologische Klinik und Poliklinik Klinikum der Universität Großhadern Ludwig-Maximilian-Universität, München, Germany; University of Chicago, Chicago, IL; Baylor Charles A. Sammons Cancer Center, Dallas, TX; Bayer HealthCare Pharmaceuticals, Montville, NJ; and Cleveland Clinic Taussig Cancer Center, Cleveland, OH.

Corresponding author: Bernard Escudier, MD, Department of Medicine, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France; e-mail: escudier{at}igr.fr.

Purpose Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in patients with renal cell carcinoma (RCC) are reported.

Patients and Methods Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated.

Results The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post–cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib.

Conclusion Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.

Written on behalf of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) Study Group.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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