Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives

Abstract

Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment with BRAF and MEK inhibitors has resulted in high objective response rates, but most responses are short-lived. Preclinical data suggest that BRAF and MEK inhibitors result in immunomodulatory changes in the tumor microenvironment; early data in murine models further suggest that these changes could enhance sensitivity to ICIs. Subsequently, the notion of combining the two therapy modalities for a more effective response was further evolved in early phase clinical trials. In this review, we analyzed the results of recent phase 2 and 3 clinical trials investigating the combination of ICIs with targeted therapy in BRAFV600-mutated advanced melanoma. Furthermore, we evaluated the results of recent studies investigating the first-line treatment sequencing of ipilimumab/nivolumab and BRAF/MEK inhibitors in these patients. We discussed the study limitations and interpreted how these recent advances could be incorporated into the treatment landscape of advanced BRAFV600-mutant melanoma.