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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-63198

Flaherty, K T; Robert, C; Hersey, P; Nathan, P; Garbe, C; Milhem, M; Demidov, L V; Hassel, J C; Rutkowski, P; Mohr, P; Dummer, R; Trefzer, U; Larkin, J; Utikal, J; Dreno, B; Casey, M; Sherman, L J; Wu, F S; Schadendorf, D (2012). Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group. New England Journal of Medicine, 367(2):107-114.

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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.
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.
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.
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.)


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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Date:20 June 2012
Deposited On:20 Jun 2012 14:44
Last Modified:07 Apr 2015 07:29
Publisher:Massachusetts Medical Society
Publisher DOI:10.1056/nejmoa1203421
PubMed ID:22663011

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