Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy

Cancer. 2019 Mar 15;125(6):884-891. doi: 10.1002/cncr.31889. Epub 2018 Dec 6.


Background: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting.

Methods: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy.

Results: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months.

Conclusions: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.

Keywords: BRAF; MEK; efficacy; melanoma; programmed cell death protein 1 (PD-1); toxicity.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Australia
  • Female
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / adverse effects
  • Male
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Middle Aged
  • Oximes / administration & dosage*
  • Oximes / adverse effects
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Pyridones / administration & dosage*
  • Pyridones / adverse effects
  • Pyrimidinones / administration & dosage*
  • Pyrimidinones / adverse effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Survival Analysis
  • Tertiary Care Centers
  • Treatment Outcome
  • United States


  • Imidazoles
  • Oximes
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • dabrafenib