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Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group

David F. McDermott, Jeffrey A. Sosman, Rene Gonzalez, F. Stephen Hodi, Gerald P. Linette, Jon Richards, James W. Jakub, Muralidhar Beeram, Stefano Tarantolo, Sanjiv Agarwala, Gary Frenette, Igor Puzanov, Lee Cranmer, Karl Lewis, John Kirkwood, J. Michael White, Chenghua Xia, Kiran Patel, Evan Hersh

From the Beth Israel Deaconess Medical Center; Dana Farber Cancer Institute, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Colorado Health Sciences Center, Aurora, CO; Washington University School of Medicine, St Louis, MO; Lutheran General Cancer Care Center, Park Ridge, IL; Lakeland Regional Cancer Center, Lakeland, FL; University of Texas Health Science Center, San Antonio, TX; Nebraska Methodist Hospital, Omaha, NB; St Luke's Health System, Bethlehem; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Carolinas Hematology-Oncology Associates, Charlotte, NC; University of Arizona Cancer Center, Tucson AZ; Onyx Pharmaceuticals, Inc, Emeryville, CA; and Bayer HealthCare Pharmaceuticals, West Haven, CT

Corresponding author: David F. McDermott, MD, Clinical Director of Biologic Therapy Program, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, East KS-159, Boston, MA; e-mail: dmcdermo{at}bidmc.harvard.edu

Purpose: This phase II study evaluated the efficacy and safety of sorafenib plus dacarbazine in patients with advanced melanoma.

Patients and Methods: This randomized, double-blind, placebo-controlled, multicenter study enrolled chemotherapy-naïve patients with stage III (unresectable) or IV melanoma. A total of 101 patients received placebo plus dacarbazine (n = 50) or sorafenib plus dacarbazine (n = 51). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1,000 mg/m² for a maximum of 16 cycles. Oral sorafenib 400 mg or placebo was administered twice a day continuously. The primary end point was progression-free survival (PFS) by independent assessment. Secondary and tertiary end points included time to progression (TTP), response rate, and overall survival (OS).

Results: Median PFS in the sorafenib plus dacarbazine arm was 21.1 weeks versus 11.7 weeks in the placebo plus dacarbazine arm (hazard ratio [HR], 0.665; P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months, and in TTP (median, 21.1 v 11.7 weeks; HR, 0.619) in favor of the sorafenib plus dacarbazine arm. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo plus dacarbazine and sorafenib plus dacarbazine arms, respectively; HR, 1.022). The regimen was well tolerated and had a manageable toxicity profile.

Conclusion: Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population.

Supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals Inc.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007 and at the 14th European Cancer Conference, Barcelona, Spain, September 23-27, 2007.

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