BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

There have been significant advances in the past few years with regard to BRAFdirected therapy. Despite these advances, resistance to BRAF monotherapy develops in the majority of patients with most patients progressing within 6 to 7 months [1–3]. A better understanding of resistance mechanisms has led to therapeutic strategies that improve responses and enhance survival, including additional MAPK blockade via combination BRAF and MEK inhibition. Thus far, such combinations (e.g. BRAF + MEK inhibition) have yielded significant improvements in the durability of response, though most patients still progress within 10 months and only a small fraction of patients achieve a CR or prolonged PR [4]. More sustained responses are clearly needed, and other combinations are currently being tested in preclinical studies and in clinical trials.

In addition to advances in targeted therapy, significant headway has been made with regard to immunotherapy for melanoma. Several immunotherapy agents are currently approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma, including cytokine-based therapy with interleukin-2 (Aldesleukin) and the immune checkpoint inhibitor targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4) called ipilimumab. Several other agents are currently under investigation in the context of clinical trials (immune checkpoint inhibitors targeting programmed death receptor 1 [PD1] and its ligand [PDL1]), and have shown promise in early phase studies [5, 6]. The advantage of immunotherapy over BRAF-directed therapy is that responses are often durable, however the drawback is that overall response rates remain low (10–15% in the case of Ipilimumab), with a minority of patients obtaining an objective response [7].

There is increasing evidence that BRAF-directed therapy may synergize with immunotherapy [8–13], with the potential to maintain high response rates while extending the durability of responses. Evidence regarding potential synergy is presented herein, and ongoing clinical trials combining these strategies are discussed. Finally, important questions are posed with regard to potential issues of toxicity, timing and sequence of the different strategies, and the duration of therapy.

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