Abstract

The management and prognosis of BRAF-mutant metastatic melanoma have changed drastically following the introduction of immune checkpoint inhibitors and molecularly targeted agents. These treatment options present different mechanisms of action and toxicities but also totally distinct kinetics of their response, including a "relatively" short-lasting benefit in subsets of patients treated with BRAF/MEK inhibitors and a lower response rate in patients treated with immune checkpoint inhibitors. BRAF/MEK inhibitors, when administered prior to or concurrently with immune checkpoint inhibitors, at least transiently alter some immunosuppressive parameters of the tumor microenvironment and theoretically improve sensitivity to immunotherapy. Preclinical data from mouse models with oncogene-addicted melanoma confirmed this beneficial immune/targeted synergy and supported the clinical testing of combinations of BRAF/MEK inhibitors and immune checkpoint inhibitors to improve the activity of upfront anti-melanoma therapies. The first positive phase III results were published in 2020, and triggered the discussion about the benefits, the limitations, as well as the possible implications of combining or sequencing targeted therapies with immune checkpoint inhibitors in everyday practice. Beginning from the interplay of immune/targeted agents within the melanoma microenvironment, this review outlines available information from the retrospective experience up to the late- stage randomized evidence on combinatorial treatments. Many clinical trials are currently underway exploring open questions about optimal timing, new immune biomarkers, and eligible patient subsets for these immune/targeted regimens. Awaiting these results, decision making in the first- line setting for BRAF-mutant melanoma is still guided by the patients' characteristics and the biological aspects of melanoma.