Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma Axel Hauschild, Sanjiv S. Agarwala, Uwe Trefzer, David Hogg, Caroline Robert, Peter Hersey, Alexander Eggermont, Stephan Grabbe, Rene Gonzalez, Jens Gille, Christian Peschel, Dirk Schadendorf, Claus Garbe, Steven O’Day, Adil Daud, J. Michael White, Chenghua Xia, Kiran Patel, John M. Kirkwood, and Ulrich Keilholz From the University of Kiel, Kiel; Charite ´ Berlin; University Hospital Benjamin Franklin, Berlin; Johannes Gutenberg Clinic-Mainz University, Mainz, Germany; Johann Wolfgang Goethe University, Frankfurt am Main; Klinikum rechts der Isar, Munich; University Hospital of Mannheim, Mannheim, Germany; University Hospi- tal of Tuebingen, Tuebingen, Germany; St Luke’s Hospital and Health Network, Bethlehem; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Univer- sity of Colorado Cancer Center, Aurora, CO; The Angeles Clinic and Research Institute, Santa Monica; Onyx Pharma- ceuticals, Emeryville, CA; H. Lee Moffitt Cancer Center, Tampa, FL; Bayer AG, West Haven, CT; University of Toronto and Princess Margaret Hospital, Toronto, Ontario, Canada; Institut Gustave-Roussy, Villejuif Cedex, France; Newcastle Mater Misericordiae Hospital, Newcastle, New South Wales, Australia; and the Erasmus University Medical Center- Daniel den Hoed Cancer Centre, Rotterdam, Netherlands. Submitted December 18, 2007; accepted December 22, 2008; published online ahead of print at www.jco.org on April 6, 2009. Supported by Bayer AG and Onyx Phar- maceuticals, Inc. A.H. and S.S.A. contributed equally to this article. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Written on behalf of the 11718 study investigators. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical Trials repository link available on JCO.org Corresponding author: Sanjiv S. Agarwala, MD, St Luke’s Cancer Center, 801 Ostrum St, Bethlehem, PA 18015; e-mail: agarwas@slhn.org. © 2009 by American Society of Clinical Oncology 0732-183X/09/2799-1/$20.00 DOI: 10.1200/JCO.2007.15.7636 A B S T R A C T Purpose This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. Patients and Methods A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m 2 plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. Results The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3 thrombo- cytopenia, diarrhea, and fatigue were more common in patients treated with sorafenib plus CP versus placebo plus CP. Conclusion In this study, the addition of sorafenib to CP did not improve any of the end points over placebo plus CP and cannot be recommended in the second-line setting for patients with advanced melanoma. Both regimens had clinically acceptable toxicity profiles with no unexpected adverse events. A trial of similar design for the first-line treatment of patients with advanced melanoma (intergroup trial E2603) is currently ongoing. J Clin Oncol 27. © 2009 by American Society of Clinical Oncology INTRODUCTION The incidence of melanoma in the United States is increasing at one of the highest rates of any form of cancer, with the current lifetime risk of one in 68. 1 Worldwide, the incidence of melanoma continues to rise at a rate of approximately 3% per year. 2 If detected and treated at an early stage, melanoma has a cure rate of approximately 90%. 3 In contrast, the prognosis for advanced metastatic disease is poor, with an average 5-year survival rate of 11% and a median survival of 6 to 12 months in patients having systemic metastases. 4-6 The effect of systemic therapy on survival for patients with advanced melanoma remains con- troversial. Although there is no standard of treat- ment for advanced melanoma, dacarbazine is the most commonly used cytotoxic agent and has an acceptable toxicity profile; however, it has a low objective response rate of 5% to 20% and a median progression-free survival (PFS) of fewer than 2 months. 7-11 Combination regimens containing multi- ple chemotherapeutic agents, various biologic agents, or both, have not improved overall survival com- pared with single-agent therapy. 9 Carboplatin and paclitaxel (CP) have shown modest activity in advanced melanoma. 12-16 Three phase II trials of paclitaxel as a single agent in ad- vanced melanoma demonstrated a mean response rate (mostly partial responses [PRs]) of approxi- mately 17%. 12,14,16 The combination of CP has been JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T © 2009 by American Society of Clinical Oncology 1 http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2007.15.7636 The latest version is at Published Ahead of Print on April 6, 2009 as 10.1200/JCO.2007.15.7636 Copyright 2009 by American Society of Clinical Oncology Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved. from 132.252.149.100. Information downloaded from jco.ascopubs.org and provided by Universitaetsklinikum Fachbibl. Medizin 2 on April 23, 2009