The combination of dabrafenib and trametinib achieves significant improvements in overall survival and progression-free survival in patients with untreated metastatic melanoma compared with treatment with vemurafenib alone, new data suggest.

An open-label randomized phase III trial showed the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib in patients with BRAF V600E or V600K mutant melanoma resulted in a significant reduction in death rates at 12 months compared with monotherapy with BRAF inhibitor vemurafenib (HR 0.69, 95% CI 0.53-0.89, P = .005).

Researchers observed a median progression-free survival rate of 11.4 months in the combination arm, compared with 7.3 months in the monotherapy arm (HR 0.56, 95% CI 0.46-0.69, P < .001), according to data presented at the 2014 International Congress for the Society for Melanoma Research.

The most common adverse event was fever, experienced by 53% of patients in the combination arm and 21% of patients in the monotherapy arm; however, there were more grade 3 and 4 adverse events noted among patients treated with vemurafenib alone.

Pyrexia was the most common reason for dose interruption or reduction in the dabrafenib-plus-trametinib group, while rash was the same for the vemurafenib group.

The study, which presented data from a preplanned interim analysis of 704 patients and 222 events, showed an overall response rate of 64% for the combination of dabrafenib and trametinib, and 51% among those treated with vemurafenib alone.

In a paper published simultaneously online Nov. 16 in the New England Journal of Medicine, researchers said that combining a BRAF inhibitor with a MEK inhibitor could address some of the limitations of monotherapy by delaying the development of resistance and reducing the incidence of BRAF inhibitor–induced skin tumors (N. Engl. J. Med. 2014 Nov. 16 [doi: 10.1056/NEJMoa1412690]).

“Together with the previously reported phase II and phase III trials of dabrafenib plus trametinib, as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,” wrote Dr. Caroline Robert of Institut Gustave Roussy, Paris, and her colleagues.

The researchers noted that more patients in the vemurafenib monotherapy arm received further anticancer therapy than in the combination arm (43% vs. 20%).

The study was supported by GlaxoSmithKline. Some authors declared grants, travel expenses, and personal fees from pharmaceutical companies including GlaxoSmithKline, and several were employees of the company.


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