Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials

The development of BRAF and MEK inhibitors (BRAFis and MEKis) and immune checkpoint inhibitors have changed the management of advanced stage melanoma and improved the outcomes of patients with this malignancy. However, both therapeutic approaches have limitations, including a limited duration of benefit in subsets of BRAF-mutant melanoma patients treated with targeted therapy and a lower overall response rate without a clear predictive biomarker in patients treated with checkpoint inhibitors. Preclinical and translational data have shown that BRAFis and MEKis alter the tumor microenvironment to make it more amenable to immunotherapy and have provided the scientific rationale for combing BRAFis and MEKis with immunotherapy. In this review, the initial studies demonstrating the impact of BRAFis and MEKis on the expression of melanoma differentiation antigens, T-cell infiltration, and the balance of immune stimulatory and immune suppressive cells and cytokines are addressed. Preclinical work on the combination of targeted therapy with BRAFis and MEKis with immunotherapy are reviewed, highlighting improved tumor responses in mouse models of BRAF-mutated melanoma treated with combinatorial strategies. Lastly, data from early clinical trials of combined targeted therapy and immunotherapy are discussed, focusing on response rates and toxicities