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

Journal Article (Journal Article)

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: identifier: NCT01673854 (CA184-240) Registered 24 August 2012.

Full Text

Duke Authors

Cited Authors

  • Amin, A; Lawson, DH; Salama, AKS; Koon, HB; Guthrie, T; Thomas, SS; O'Day, SJ; Shaheen, MF; Zhang, B; Francis, S; Hodi, FS

Published Date

  • 2016

Published In

Volume / Issue

  • 4 /

Start / End Page

  • 44 -

PubMed ID

  • 27532019

Pubmed Central ID

  • PMC4986368

International Standard Serial Number (ISSN)

  • 2051-1426

Digital Object Identifier (DOI)

  • 10.1186/s40425-016-0148-7


  • eng

Conference Location

  • England