Therapeutic Advances and Treatment Options in Metastatic Melanoma

Over the past several years, management of advanced melanoma has been transformed by the development and approval of novel therapeutic approaches. Genetically targeted therapies are now effective treatment options for the approximately 50% of patients whose melanomas harbor activating point mutations in BRAF. Combination regimens of small-molecule inhibitors have been developed to delay the onset of acquired resistance. Specifically, combined BRAF and MEK inhibition improves response rates and survival compared with single-agent BRAF inhibitors and has now received regulatory approval. During the same time frame, excitement has surrounded the development of immunotherapy with checkpoint inhibitors. New immune checkpoint inhibitors blocking cytotoxic T lymphocyte antigen-4 (CTLA4) or programmed death-1 receptor/ligand (PD-1/PD-L1) improve patient outcomes by promoting an antitumor immune response. These agents have been associated with an increasing number of durable responses and are being developed in various combinations. In this review, we discuss the development of these targeted and immune therapies, review current patient management, and highlight future directions.