MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma

Superficial spreading melanoma

Patients with previously untreated BRAF V600E or V600K metastatic melanoma had a significant improvement in overall survival when treated with a combination of a BRAF inhibitor and a MEK inhibitor compared with treatment with a BRAF inhibitor alone, according to the results of a study published in the January 1 issue of the New England Journal of Medicine.

In fact, patients treated with dabrafenib and trametinib had a 31% relative risk reduction for death compared with patients assigned monotherapy with the BRAF inhibitor vemurafenib, with no significant increase in toxicity.

“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 study author Caroline Robert, MD, PhD, Gustave Roussy and INSERM Unité 981, Villejuif-Paris Sud, and colleagues.

The phase III trial included 704 patients who were randomly assigned to first-line therapy with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily (n = 352) or vemurafenib 960 mg twice daily (n = 352).

An interim analysis was performed after 222 events occurred, with 100 deaths in the combination arm and 122 in the monotherapy arm (HR for death in the combination arm = 0.69; 95% CI, 0.53-0.89; P = .005). The 12-month overall survival was 72% for patients assigned combination therapy compared with 65% for patients assigned monotherapy.

Patients assigned to dabrafenib and trametinib also had a significantly longer progression-free survival compared with those patients assigned vemurafenib (11.4 months vs 7.3 months; P < .001). The objective response rate for the combination therapy was 64% compared with 51% for monotherapy (P < .001).

“Notably, the rate of complete response was also significantly higher in the combination-therapy group than in the vemurafenib group (13% vs 8%; P = .02) in a post-hoc analysis,” the researchers wrote.

The researchers conducted a safety analysis in 699 patients who received at least one dose of the study drugs. It was determined that the rates of serious adverse events (91% for combination vs 98% for monotherapy) and discontinuation due to the study drug (13% vs 12%) were similar in the two study groups.

“Skin adverse effects were less frequent in the combination-therapy group, especially the events that are linked to a paradoxical activation of the MAPK pathway, including both benign and malignant skin tumors,” the researchers wrote. “This finding is in accordance with preclinical models showing that the addition of MEK inhibitors may downregulate the BRAF inhibitor–induced paradoxical activation of the MAPK pathway.”

This trial was funded by GlaxoSmithKline.