Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma.

• Type of Material: Article
• Authors: Asim Amin, Levine Cancer Institute; David Lawson, Emory University; April K.S. Salama, Duke Cancer Institute; Henry B. Koon, Case Western Reserve University; Troy Guthrie, Baptist Cancer Institute; Sajeve S. Thomas, MD Anderson Cancer Center; Steven J. O'Day, John Wayne Cancer Institute; Montaser F. Shaheen, University of New Mexico; Bin Zhang, Bristol-Myers Squibb; Stephen Francis, Bristol-Myers Squibb; F. Stephen Hodi, Dana-Farber Cancer Institute
• Language: English
• Date: 2016-08-16
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2016
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40425-016-0148-7
• Title of Journal or Parent Work: Journal for ImmunoTherapy of Cancer
• ISSN: 2051-1426
• Volume: 4
• Start Page: 44
• End Page: 44
• Grant/Funding Information: Bristol-Myers Squibb Co.
• Keywords: BRAF inhibitor; Ipilimumab; Melanoma; Immunotherapy; Immune checkpoint inhibitor; Vemurafenib; CTLA-4; Targeted agent
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

Abstract

BACKGROUND: Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma. METHODS: This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI. RESULTS: All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months. CONCLUSIONS: VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012.