E Fulchiero, A Jimeno
Drugs of Today 2014, 50 (12): 791-802
Until recently, a treatment for advanced melanoma with a tolerable side effect profile has remained elusive. Therefore, despite its relatively rare occurrence, melanoma continues to cause the majority of skin cancer deaths, with less than 15% of those affected with late-stage disease surviving 10 years or more. Historically, the mainstay of treatment has been single-agent chemotherapy or immunotherapy with the alkylating agent dacarbazine and interleukin-2 or interferon. Cytotoxic chemotherapy with dacarbazine demonstrated poor response rates and little or no survival benefit, whereas IL-2 and interferon, although showing durable responses, are associated with poor side effect profiles (1, 2). However, with the elucidation of the molecular biology and oncogenic pathways involved in melanoma, agents targeted against mutations in the mitogen-activated protein kinase (MAPK) pathway including BRAF and MEK inhibitors have demonstrated prolonged survival and more manageable side effect profiles relative to traditional chemotherapy. Simultaneously, an evolved understanding of the immunologic basis for the development and regression of melanoma lead to the discovery of immune checkpoint inhibitors, which confer a similar survival benefit. Foremost among these was ipilimumab, a monoclonal antibody against the negative regulatory checkpoint molecule cytotoxic T-lymphocyte protein 4 (CTLA-4), which was the first drug in the management of metastatic melanoma to confer a survival benefit. However, treatment is complicated by a high rate of grade 3 and 4 immune-related adverse events and limited response. Nivolumab, a fully human monoclonal antibody against programmed cell death protein 1 (PD-1), has shown a survival benefit in an open-label phase II trial, and was the first PD-1 inhibitor to be approved worldwide. With a favorable side effect profile and ongoing trials in combination with extant therapies, nivolumab shows substantial potential to further augment the options for an effective treatment in malignant melanoma.

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