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www.thelancet.com/oncology Published online November 21, 2014 http://dx.doi.org/10.1016/S1470-2045(14)71138-6 1

Lancet Oncol 2014

Published OnlineNovember 21, 2014 http://dx.doi.org/10.1016/S1470-2045(14)71138-6

For the study by Robert and colleagues see N Engl J Med 2014; published online November 16. DOI:10.1056/NEJMoa1412690

A new standard of care for metastatic melanoma?Combination of a BRAF inhibitor and a MEK inhibitor signifi cantly improves survival compared with BRAF inhibitor monotherapy in treatment-naive patients with BRAF-mutated metastatic melanoma, according to a new study.

Metastatic melanoma with BRAF V600E or V600K mutations responds well to BRAF inhibitors like dabrafenib but acquired resistance develops frequently through reactivation of the mitogen-activated protein kinase (MAPK) pathway. Additionally, the use of BRAF inhibitors alone might result in the development of secondary skin tumours, originating from a paradoxical activation of the MAPK pathway in cells without a BRAF mutation. Combining BRAF inhibitor with a MEK inhibitor like trametinib helps with both problems.

This open-label, randomised, phase 3 study including 704 patients

assessed the safety and effi cacy of the combination treatment dabrafenib and trametinib compared with vemurafenib (another BRAF inhibitor) alone. The study was stopped early because of effi cacy at a prespecifi ed interim analysis. Combination treat-ment improved overall survival at 12 months (72% vs 65%, hazard ratio [HR] for death 0·69; 95% CI 0·53–0·89; p=0·005) and increased median progression-free survival (11·4 vs 7·3 months, HR 0·56; 95% CI 0·46–0·69; p<0·001). The objective response rate was 64% in the combination treatment group and 51% in the vemurafenib group (p<0·001). Although the incidence of severe adverse reactions were similar in both groups, cutaneous adverse events of any grade were lower in the combination group (fi ve [1%] vs 63 [18%]).

Lead author Caroline Robert (Gustave Roussy Cancer Institute,

Villejuif, France) commented, “The combination of BRAF inhibitor and MEK inhibitor should be the standard of care in this population of patients against which new candidate drugs developed in further studies should be evaluated.”

Simone M Goldinger (Zurich University Hospital, Zurich, Switzerland) said that further vali-dation studies are not needed for this combin ation and added, “Important issues that need to be addressed and further studied include the optimal treatment duration in patients that respond to the combination treatment, the optimal treatment schedule to further delay development of resistance, [and] how to favourably integrate immuno-therapy treatments to the current combination therapy.”

Sharan Prakash Sharma