Combination BRAF-MEK Inhibition With Dabrafenib and Trametinib for BRAF-Mutant Melanoma

Philip Friedlander, MD, PhD

Stage IV melanoma is an aggressive malignancy with a median survival shorter than 1 year. The identification of activating mutations in a component of the mitogen activated protein kinase (MAPK) pathway called BRAF in 40% to 60% of melanomas has allowed for the development of efficacious therapies that inhibit the activity of the pathway. Targeted inhibition of BRAF with vemurafenib or dabrafenib or direct inhibition of MEK with trametinib confers high response rates and statistically significant survival benefits relative to treatment with traditional chemotherapy. The FDA has approved these agents as monotherapies for the treatment of metastatic melanoma containing a V600 BRAF mutation. Phase II data suggest that treatment with the combination of a BRAF and a MEK inhibitor, dabrafenib plus trametinib, can further increase the rate and durability of treatment responses and lengthen the survival benefit conferred by single-agent treatment. Combined treatment with dabrafenib and trametinib was conditionally approved by the FDA in January 2014 for the treatment of unresectable and metastatic melanoma expressing a V600E or V600K BRAF mutation.

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