Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. Issue 1 (16th August 2016)

• Record Type: Journal Article
• Authors: Amin, Asim; Lawson, David H.; Salama, April K.S.; Koon, Henry B.; Guthrie, Troy; Thomas, Sajeve S.; O'Day, Steven J.; Shaheen, Montaser F.; Zhang, Bin; Francis, Stephen; Hodi, F. Stephen
• Is Part Of: Journal for immunotherapy of cancer. Volume 4:Issue 1(2016)
• Publication Date: 2016-08-16
• Subjects: Vemurafenib -- Ipilimumab -- Melanoma -- CTLA-4 -- Immune checkpoint inhibitor -- BRAF inhibitor -- Immunotherapy -- Targeted agent; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-016-0148-7
• Languages: English
• ISSNs: 2051-1426

Abstract

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