FDA Priority Review for Metastatic Melanoma Oral Combination

The combination of two oral targeted agents, dabrafenib (Tafinlar) and trametinib (Mekinist), has been given a priority review by the US Food and Drug Administration (FDA) for the treatment of BRAF V600 (both V600E and V600K)–positive metastatic melanoma. A decision by the FDA is expected in January 2014.

Both dabrafenib and trametinib were each individually approved as monotherapy for patients with BRAF V600E–positive metastatic melanoma in May of this year. The THxID BRAF assay, developed by France-based bioMerieux, Inc, was also approved for detecting of BRAF V600E tumor mutations.

Approximately 40% of metastatic melanoma patients harbor a BRAF mutation. Both drugs target the mitogen-activated protein kinase (MAPK) pathway. Dabrafenib directly targets the V600E-mutated BRAF protein. Trametinib is an inhibitor of the MEK protein in the MAPK pathway. MEK is known to be activated in melanoma, downstream of the BRAF protein. Another V600E BRAF inhibitor, vemurafenib (Zelboraf), is also approved for BRAF V600E-mutated metastatic melanoma.

GlaxoSmithKline, the company developing the combination of dabrafenib plus trametinib, announced that the application for the combination therapy is based on a randomized phase I/II trial that compared the combination with dabrafenib monotherapy in patients with BRAF V600–mutated advanced melanoma.

The results of the phase I/II dabrafenib/trametinib combination trial were previously published in the New England Journal of Medicine. Median progression-free survival was 9.4 months in the combination arm compared with 5.8 months in the dabrafenib alone arm (HR = 0.39, P < .001). Patients were treated with a once-daily 2 mg trametinib dose combined with 150 mg of dabrafenib twice daily. These are the same approved doses for monotherapy use. Of the patients taking the combination, 76% had a partial or complete response compared with 54% of patients treated with dabrafenib alone (P = .03).

Cutaneous squamous cell carcinoma, a side effect of BRAF inhibitor monotherapy is lower in patients treated with the combination. In the phase I/II trial, 7% of patients receiving the combination had cases of cutaneous squamous cell carcinoma compared with 19% of patients taking dabrafenib (P = .09).

Three ongoing phase III trials are currently investigating the dabrafenib/trametinib combination in melanoma, two in metastatic melanoma, and one as an adjuvant treatment. The COMBI-v trial is comparing overall survival of metastatic melanoma patients treated with either the dabrafenib/trametinib combination or vemurafenib monotherapy in almost 700 patients worldwide. Another trial is comparing progression-free survival of the dabrafenib/trametinib combination with dabrafenib monotherapy. The COMBI-AD trial is investigating the efficacy of the dabrafenib/trametinib compared with placebo in patients with surgically resected melanoma.