Clinical Utility of BRAF-Targeted Therapy in Melanoma

The identification of BRAF^V600mutations in melanoma rapidly translated into a search for strategies to exploit this recurrent genetic alteration. The selective BRAF inhibitors, vemurafenib and dabrafenib have demonstrated impressive antitumor activity with objective response rates of approximately 50 % and improved progression-free and/or overall survival compared to cytotoxic chemotherapy. The MEK inhibitor trametinib also subsequently demonstrated improved survival compared to chemotherapy. Acquired resistance, however, has limited the long-term antitumor efficacy of these therapies. Combined BRAF and MEK inhibition represents one strategy to delay the onset of resistance and potentially extend survival. Additional BRAF and MEK inhibitors and combinations are being developed with a goal of improving outcomes further. In this chapter, we review the development of approved BRAF and MEK inhibitors, the experience with combination therapy, and special clinical situations for BRAF-targeted therapy.