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

Asim Amin, David H. Lawson, April K.S. Salama, Henry B. Koon, Troy Guthrie, Sajeve S. Thomas, Steven J. O'Day, Montaser F. Shaheen, Bin Zhang, Stephen Francis, F. Stephen Hodi

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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:

Original languageEnglish (US)
Article number44
JournalJournal for ImmunoTherapy of Cancer
Issue number1
StatePublished - Aug 16 2016
Externally publishedYes


  • BRAF inhibitor
  • CTLA-4
  • Immune checkpoint inhibitor
  • Immunotherapy
  • Ipilimumab
  • Melanoma
  • Targeted agent
  • Vemurafenib

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


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