Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study

Ann Oncol. 2017 May 1;28(5):1137-1144. doi: 10.1093/annonc/mdx040.


Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study.

Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations.

Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation.

Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. NCT01689519.

Keywords: MEK inhibition; cobimetinib; melanoma; safety.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Azetidines / administration & dosage*
  • Azetidines / adverse effects
  • Disease-Free Survival
  • Drug-Related Side Effects and Adverse Reactions / classification
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Humans
  • Indoles / administration & dosage*
  • Indoles / adverse effects
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics*
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Middle Aged
  • Mutation
  • Piperidines / administration & dosage*
  • Piperidines / adverse effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Vemurafenib


  • Azetidines
  • Indoles
  • Piperidines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases
  • cobimetinib

Associated data