The Promise of Molecularly Targeted and Immunotherapy for Advanced Melanoma

Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations. Mutational oncogenic "drivers" may be targeted with chronically administered, oral kinase inhibitors, currently consisting of the mitogen-activated protein kinase (MAPK) inhibitor combinations of BRAF plus MEK-targeted drugs. These agents work quickly to relieve symptoms and induce remissions but generally have limited durations of disease control. Immunotherapies include the immune checkpoint inhibitors that block CTLA4 or PD-1-negative immune signaling as well as interleukin-2, a cytokine that stimulates T lymphocytes and natural killer cells. A combination of CTLA4 plus PD-1 blockade has the highest activity ever reported for metastatic melanoma, at the cost of high autoimmune-like toxicities. However, immunotherapies of this type may provide durable responses and even cure a subset of patients. Thus, these immunotherapeutic agents are recommended as first-line therapy for most patients with advanced melanoma. Patients with rapidly progressive, symptomatic melanoma whose tumor carries a BRAF mutation may benefit more from initial therapy with combined MAPK inhibitors.