Improved survival with MEK inhibition in BRAF-mutated melanoma.

Abstract

BACKGROUND:

Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.

METHODS:

In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.

RESULTS:

Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.

CONCLUSIONS:

Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).

• Authors: Keith T Flaherty, Caroline Robert, Peter Hersey, Paul Nathan, Claus Garbe, Mohammed Milhem, Lev V Demidov, Jessica C Hassel, Piotr Rutkowski, Peter Mohr, Reinhard Dummer, Uwe Trefzer, James M G Larkin, Jochen Utikal, Brigitte Dreno, Marta Nyakas, Mark R Middleton, Jürgen C Becker, Michelle Casey, Laurie J Sherman, Frank S Wu, Daniele Ouellet, Anne-Marie Martin, Kiran Patel, Dirk Schadendorf, METRIC Study Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 367 Issue 2 Pg. 107-14 (Jul 12 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 22663011 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• trametinib
• MAP2K2 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Disease-Free Survival
• Female
• Humans
• Intention to Treat Analysis
• Kaplan-Meier Estimate
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Male
• Melanoma (drug therapy, genetics, mortality)
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Pyridones (adverse effects, therapeutic use)
• Pyrimidinones (adverse effects, therapeutic use)
• Young Adult