Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor

J Clin Oncol. 2013 Feb 1;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17.

Abstract

Purpose: BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.

Patients and methods: This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.

Results: In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.

Conclusion: Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

Trial registration: ClinicalTrials.gov NCT01037127.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / therapeutic use*
  • Disease-Free Survival
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • Male
  • Melanoma / blood
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Middle Aged
  • Mutation* / drug effects
  • Neoplasm Staging
  • Proto-Oncogene Proteins B-raf / genetics*
  • Pyridones / administration & dosage
  • Pyridones / adverse effects
  • Pyridones / blood
  • Pyridones / therapeutic use*
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / adverse effects
  • Pyrimidinones / blood
  • Pyrimidinones / therapeutic use*
  • Skin Neoplasms / blood
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2

Associated data

  • ClinicalTrials.gov/NCT01037127