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

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 960mg twice daily for 6weeks followed by IPI 10mg/kg every 3weeks for 4 doses (induction), then every 12weeks (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 15.3months, median overall survival was 18.5months. Median progression-free survival was 4.5months. Conclusions: VEM (960mg twice daily for 6weeks) followed by IPI 10mg/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