Unprecedented responses to newly available treatments for metastatic melanoma have dramatically changed the therapeutic landscape of this disease during the last decade, highlighted by eight new US FDA approved therapies since 2011. Two approaches include modulation of the immune system with checkpoint inhibitors and targeting oncogenic drivers of melanoma using BRAF and MEK inhibitors (BRAFi and MEKi). As these therapies show more promise, the number of clinical trials exploring various combinations continues to increase. There are compelling preclinical and clinical data that provide a rationale for combining targeted agents and immune checkpoint inhibitors. While trials are ongoing, early results appear favorable. Significant challenges consist of determining optimal dosage, timing and sequencing, identification of candidates for new combinations, and attempting to individualize therapy while balancing toxicity with clinical benefit.
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