Immunotherapy Combinations With Checkpoint Inhibitors in Metastatic Melanoma: Current Approaches and Future Directions

Based on the complexity of the immune response to cancer and the mechanisms of tumor evasion, it is likely that therapeutic modulation of multiple immune-mediated pathways will be needed to maximally induce tumor regression in patients with advanced melanoma. The rationale of using combination checkpoint inhibitor-based regimens may include the concomitant effects on re-activation of T cells, increased trafficking of tumor reactive lymphocytes into the tumor tissue, and enhanced killing of cancer cells. The administration of nivolumab in combination with ipilimumab demonstrated increased response rates, tumor shrinkage, and median progression-free survival using combined therapy compared with either treatment alone. Although toxicity was also increased, this trial established proof of principle that combination immunotherapy could enhance the efficacy seen with single-agent programmed cell death protein-1 (PD-1) pathway blockade for the unselected patient. Current and future trials are evaluating alternative schedules and other combinations of immunotherapies to determine if they could provide similar efficacy with less toxicity. In addition, efforts are underway to determine how best to integrate combination immunotherapy with other treatment approaches for patients with advanced melanoma.