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

SIMPLE SUMMARY: With the development of immunotherapies and targeted therapies in the last years, there has been great progress in the outcome of patients with metastatic melanoma. One of the current challenges is to optimize the treatment efficacy, to overcome resistance and to prevent disease relapses. This review analyzed the appropriate treatment sequence and the potential of the triple combination of immunotherapy and targeted therapy in BRAFV600-mutated melanoma. We summarized the results from phase 2 and 3 clinical trials investigating these treatment modalities in patients with advanced melanoma as well as in specific subpopulations in casu those with active brain metastases. We analyzed the study designs, the treatment efficacy in sequential treatment and in triple combination as well as the observed toxicity profile. In addition, we identified specific indications and limitations of triple combination in advanced BRAFV600 mutant melanoma. 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.