Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response

Oncotarget. 2016 Aug 30;7(35):56619-56627. doi: 10.18632/oncotarget.10651.

Abstract

Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.

Keywords: BRAF mutation; ipilimumab; melanoma; sequential treatment; toxicity.

Publication types

  • Case Reports

MeSH terms

  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biopsy
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / secondary
  • DNA, Neoplasm / blood
  • Fatal Outcome
  • Gastrointestinal Tract / drug effects*
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / adverse effects*
  • Ipilimumab / adverse effects*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • Male
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Middle Aged
  • Mutation
  • Neoplastic Cells, Circulating / metabolism
  • Oximes / administration & dosage
  • Oximes / adverse effects*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Pyridones / administration & dosage
  • Pyridones / adverse effects*
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / adverse effects*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Immunological
  • DNA, Neoplasm
  • Imidazoles
  • Ipilimumab
  • Oximes
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases
  • dabrafenib