Current options and future directions in the systemic treatment of metastatic melanoma

Systemic treatment options for metastatic melanoma have historically been limited, with conventional cytotoxic chemotherapies demonstrating only modest benefit. Recent advances, however, have dramatically changed the treatment landscape and can be considered in 2 general categories: immunotherapeutic approaches that enhance antitumor immunity, and targeted therapeutic approaches that block oncogenic driver mutations. Immunotherapy with antibodies that block cytotoxic T-lymphocyte antigen 4 and programmed death-1 receptor can result in durable responses in a subset of patients. These treatments may be considered for patients irrespective of their mutational status, and ongoing research continues to investigate biomarkers associated with clinical outcomes. Side effects of these agents result from immune-mediated reactions involving various organ sites and can include: diarrhea, rash, hepatitis, and endocrinopathies. For patients whose melanoma harbors a BRAF mutation, targeted therapy with BRAF and MEK inhibitors has the potential for rapid tumor regression in the majority of patients, and some patients with KIT mutations can also respond to appropriately targeted therapy. Unfortunately, most patients' responses to targeted agents are transient with disease progression ultimately ensuing owing to the emergence of a number of mechanisms of resistance. This review begins with a description of the traditional agents used to treat metastatic melanoma, then focuses on the mechanism of action, toxicity profile, and efficacy data for the recently approved immunotherapeutic and targeted therapeutic agents. Novel approaches in clinical development are also included because expectations are high that these new agents will ultimately have an important role in the treatment of advanced melanoma.