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A Single-Arm, Open-Label, Expanded Access Study of Vemurafenib in Patients With Metastatic Melanoma in the United States

Flaherty, Lawrence MD*; Hamid, Omid; Linette, Gerald; Schuchter, Lynn§; Hallmeyer, Sigrun; Gonzalez, Rene; Cowey, C. Lance#; Pavlick, Anna**; Kudrik, Fred††; Curti, Brendan‡‡; Lawson, David§§; Chapman, Paul B.∥∥; Margolin, Kim¶¶; Ribas, Antoni##; McDermott, David***; Flaherty, Keith†††; Cranmer, Lee‡‡‡; Hodi, F. Stephen§§§; Day, Bann-Mo∥∥∥; Linke, Rolf∥∥∥¶¶¶; Hainsworth, John###

doi: 10.1097/PPO.0000000000000024
From the Industry: Expanded Access Program Experience for Vemurafenib

Purpose This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAFV600-mutated melanoma (August 2011).

Patients and Methods Eligible patients had metastatic melanoma with a BRAFV600 mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily.

Results Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non–central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation.

Discussion This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAFV600 mutation–positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

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From the *Karmanos Cancer Center, Wayne State University, Detroit, MI; †The Angeles Clinic and Research Institute, Los Angeles, CA; ‡Washington University, St Louis, MO; §University of Pennsylvania, Philadelphia, PA; ∥Oncology Specialists S.C., Park Ridge, IL; ¶University of Colorado Cancer Center, Aurora, CO; #Baylor Sammons Cancer Center, Texas Oncology, PA, Dallas, TX; **NYU Medical Center, New York, NY; ††South Carolina Oncology Associates, Columbia, SC; ‡‡Providence Portland Medical Center, Portland, OR; §§Winship Cancer Institute, Emory University, Atlanta, GA; ∥∥Memorial Sloan Kettering Cancer Center, New York, NY; ¶¶Seattle Cancer Care Alliance, Seattle, WA; ##UCLA School of Medicine, Los Angeles, CA; ***Beth Israel Deaconess Medical Center and †††Massachusetts General Hospital, Boston, MA; ‡‡‡University of Arizona Cancer Center, Tucson, AZ; §§§Dana Farber Cancer Institute, Boston, MA; ∥∥∥Genentech, San Francisco, CA; ¶¶¶The SFJ Pharma Group, Pleasanton, CA; and ###Sarah Cannon Research Institute, Nashville, TN.

Conflicts of Interest and Source of Funding: Support for third-party writing assistance for this manuscript was provided by Roche/Genentech, Inc. L.F. has received grant support and has served on the board of Merck; has consulted for Roche-Genentech, BMS, GSK, Genomic Health, and Merck; and has received payment for lectures for Roche/Genentech. O.H. has received grant support from Genentech and is a consultant and has received payment for speaker bureaus for Genentech. G.L. is a speaker for Roche/Genentech. S.H. is a speaker for Novartis and BMS. R.G. has received grant support from Roche/Genentech and has been a past consultant and received past support for travel for Roche/Genentech. C.L.C. has consulted and been a speaker for Roche/Genentech. A.P. has received grant support and financial support for being a consultant and providing review activities. B.C. has been a past consultant for BMS and Prometheus Pharmaceuticals and is awaiting grants from Prometheus Pharmaceuticals and the National Institutes of Health. D.L. has attended advisory boards for Roche/Genentech, has received support for study expenses, and has received grants for ongoing clinical trials. P.B.C. has received grant and travel support and has consulted for Genentech/Roche. K.M. has received grant support from Roche/Genentech. A.R. has consulted for Roche/Genentech, with the honoraria paid to his institution, and received financial support for travel. D.M. has received financial support for past consultancy. K.F. received grant support from and consults for Roche/Genentech. L.C. has received grant support from Roche/Genentech, with funds going to his institution, is a consultant for GSK and Merck, is on a speaker bureau; is a consultant for Roche/Genentech, Merck, BMS, and Prometheus; and has received research funding from Roche/Genentech and BMS for study protocols, with funds going to his institution. F.S.H. has received financial support for travel to meetings, served as a nonpaid consultantto Roche/Genentech, and received clinical trial support from Genentech/Roche. B.-M.D. is an employee of Genentech Inc and has received stock/stock options. R.L. is a previous employee of Roche/Genentech and received stock/stock options. J.H. received grant support from Roche/Genentech. F.K. and L.S. have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Reprints: Lawrence Flaherty, MD, Division of Hematology and Oncology, Karmanos Cancer Institute, 4100 John R-4HWCRC, Detroit, MI 48201. E-mail:

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© 2014 by Lippincott Williams & Wilkins