Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study

Eur J Cancer. 2018 Mar:91:116-124. doi: 10.1016/j.ejca.2017.12.007. Epub 2018 Jan 19.

Abstract

Background: Most metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy.

Patients and methods: One hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated.

Results: The median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43.3%: complete response (CR) 2.6%, partial response (PR) 40.7%, stable disease (SD) 24.8% and progressive disease 31.9%, 3 missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites (hazard ratio [HR] = 1.32 for each additional organ with metastases, P < .001), lactic dehydrogenase (HR = 1.37 for each multiple of the upper normal limit, P < .001), while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone (HR = 0.5, P = .006).

Conclusion: Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.

Keywords: BRAF inhibitors; BRAFi; MEKi; Metastatic melanoma.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Australia
  • Clinical Decision-Making
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm
  • Europe
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / mortality
  • Melanoma / secondary
  • Middle Aged
  • Proportional Hazards Models
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Retrospective Studies
  • Risk Factors
  • Signal Transduction / drug effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Time Factors
  • Treatment Outcome
  • United States

Substances

  • Protein Kinase Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases