title: Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012.
authors.affiliation: Levine Cancer Institute, Carolinas Healthcare System, Medical Oncology, 1021 Morehead Medical Drive, Charlotte, NC 28204 USA.
authors.forename: Asim
authors.initials: A
authors.lastname: Amin
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Lawson
authors.affiliation: Duke Cancer Institute, Durham, NC USA.
authors.forename: April K S
authors.initials: AK
authors.lastname: Salama
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH USA.
authors.forename: Henry B
authors.initials: HB
authors.lastname: Koon
authors.affiliation: Baptist Cancer Institute, Jacksonville, FL USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Guthrie
authors.affiliation: MD Anderson Cancer Center Orlando, Orlando, FL USA.
authors.forename: Sajeve S
authors.initials: SS
authors.lastname: Thomas
authors.affiliation: John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, NM USA.
authors.forename: Montaser F
authors.initials: MF
authors.lastname: Shaheen
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ USA ; Current Address: KBP BioSciences, Princeton, NJ USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Francis
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
keywords: BRAF inhibitor; CTLA-4; Immune checkpoint inhibitor; Immunotherapy; Ipilimumab; Melanoma; Targeted agent; Vemurafenib