Advances in the Systemic Treatment of Metastatic Melanoma
Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes.
Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma-including dacarbazine, temozolomide (Temodar), fotemustine, carboplatin, paclitaxel, and interleukin-2-demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials. Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes. Within this rich context of effective agents, the challenge for clinicians and investigators will be to develop predictive biomarkers of response, the optimal sequence of therapy for individual patients, and effective combinations. An additional challenge will be to find the appropriate venue and populations to test promising new agents arising from substantial advances in our understanding of molecular alterations in melanoma cells, of mechanisms of resistance to current agents, and of tumor-host immune interactions.
Introduction
Before 2011, no systemic treatment for unresectable locally advanced stage III or stage IV melanoma had been consistently proven to increase median survival, and no large studies had compared existing treatments to best supportive care. In large controlled randomized trials, the median survival was consistently in the range of 8 to 11 months.[1-3] High-dose interleukin-2 (IL-2) was approved for the treatment of metastatic melanoma based on durable tumor remissions in approximately 5% of patients, but it can only be administered to those with excellent performance status and normal organ function, and to date it has not been compared with any other standard treatment in a randomized trial.[4]
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Agents/Approaches Contributing to Treatment Advances in Metastatic Melanoma