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Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib

Caroline Robert, M.D., Ph.D., Boguslawa Karaszewska, M.D., Jacob Schachter, M.D., Et al.

N Engl J Med 2015; 372:30-39 January 1, 2015

Editor's comments: Prof Paolo A. Ascierto
The advent of BRAF inhibitors for the treatment of metastatic melanoma harboring the BRAF V600 mutation has allowed to achieve significant results in terms of PFS and OS compared to standard chemotherapy. Unfortunately, the principal limitation of these treatments is the occurrence of acquired resistance due to the reactivation of the MAPK pathway. In addition, it is known that the use of BRAF inhibitors may result in the development of secondary skin tumors, due to a paradoxical activation of the MAPK pathway in cells with without a BRAF mutation but with NRAS mutated. The combination of a BRAF inhibitor with a MEK inhibitor could reduce both of these limitations of BRAF inhibitors monotherapy. The study presented in this manuscript is an open-label, randomized, phase 3 study enrolling 704 patients with unresectable stage IIIC or IV melanoma with BRAF V600E or V600K mutations, designed to evaluate the effect on overall survival of the combination therapy with dabrafenib plus trametinib versus vemurafenib monotherapy. The median overall survival was 17.2 months in the vemurafenib group while was not reached in the combination-therapy group; the risk reduction for progression or death was of 31%. A significant improvements were found also in terms of ORR and PFS. Skin adverse events were less frequent in the combination-therapy group: cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% in the vemurafenib group. This finding confirms that the addition of MEK inhibitors may delay the treatment resistance and reduce the occurrence of skin cancers.

BACKGROUND
The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.

METHODS
In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.

RESULTS
At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.

CONCLUSIONS
Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.)