title: Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors.
abstract: BACKGROUND
  The immunotherapy (IT) agents ipilimumab and interleukin-2 as well as BRAF inhibitors (BRAFi) vemurafenib and dabrafenib, with or without trametinib (MEK inhibitors), are all FDA-approved treatments for BRAF metastatic melanoma, but there are few studies to guide optimal sequencing. This retrospective analysis describes the outcomes of patients treated with either BRAFi before IT or IT before BRAFi.
  
  
  METHODS
  A cohort of patients treated with BRAFi alone or with MEK inhibitor was retrospectively identified. Response rate (RR), overall survival (OS), and progression-free survival (PFS) were evaluated for the entire cohort, subdivided by BRAFi prior to or after IT.
  
  
  RESULTS
  RR and median PFS and OS calculated from commencement of BRAFi following IT (N = 32) were 57%, 6.7 months (95% confidence interval [CI] = 4.3-9.1 months), and 19.6 months (95% CI = 10.0-undefined months), respectively; whereas for BRAFi initially (N = 242) were 66%, 5.6 months (95% CI = 4.7-6.8 months), and 13.4 months (95% CI = 10.1-17.0 months). Results were similar when controlled for prognostic variables. A total of 193 patients discontinued BRAFi, with OS of 2.9 months (range of 1.8-4.4 months) from day of BRAFi discontinuation. Forty patients subsequently received IT with ipilimumab. Only half could complete 4 doses of ipilimumab; PFS with ipilimumab was 2.7 months (95% CI = 1.8-3.1 months) and OS was 5.0 months (95% CI = 3.0-8.8 months).
  
  
  CONCLUSIONS
  In this retrospective analysis, prior treatment with IT does not appear to negatively influence response to BRAFi. Outcomes for IT with ipilimumab following BRAFi discontinuation are poor. Randomized controlled trials are needed to define if sequencing IT prior to BRAFi therapy is superior to sequencing BRAFi prior to IT.
authors.affiliation: Department of Medicine, Division of Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Allison
authors.initials: A
authors.lastname: Ackerman
authors.forename: Oliver
authors.initials: O
authors.lastname: Klein
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Nageatte
authors.initials: N
authors.lastname: Ibrahim
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.forename: Anasuya
authors.initials: A
authors.lastname: Gunturi
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D000074324:Ipilimumab; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: BRAF; ipilimumab; melanoma; sequencing; vemurafenib