Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition

J Immunother. 2017 Jan;40(1):31-35. doi: 10.1097/CJI.0000000000000148.


Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P=0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD-1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited >6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (<6 mo) on BRAFi (34% vs. 15%, P=0.04). We conclude that either BRAFi or anti-PD-1 may be effective regardless of treatment sequence in patients with BRAF-mutant melanoma, but clinical outcomes to front-line therapy are superior. In addition, we suggest a shared "responder phenotype" between BRAFi and anti-PD-1.

Publication types

  • Comparative Study
  • Multicenter Study

MeSH terms

  • Antibodies, Blocking / therapeutic use*
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • B7-H1 Antigen / antagonists & inhibitors
  • Cohort Studies
  • Controlled Before-After Studies
  • Drug Therapy, Combination
  • Female
  • Humans
  • Ipilimumab / therapeutic use*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • Male
  • Melanoma / genetics*
  • Melanoma / mortality
  • Melanoma / therapy
  • Middle Aged
  • Mutation / genetics*
  • Programmed Cell Death 1 Receptor / immunology
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Survival Analysis


  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • Ipilimumab
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases