The clinical outcome of BRAF-mutated advanced
melanoma has been improved by both
molecular targeted therapies and
immune checkpoint inhibitors. Long-term follow-up data reveal durable clinical responses in patients receiving first-line combinations of BRAF inhibitors plus
MEK inhibitors, particularly those showing a complete response. Clinical outcomes are also associated with the
lactate dehydrogenase levels and the number of metastatic organs. Although brain
metastasis is frequently difficult to control, systemic
therapy is preferred in cases with small and asymptomatic
brain metastases associated with progressive extra-cranial disease. Control of intra-cranial disease with BRAF inhibitors plus
MEK inhibitors is comparable with that of
immune checkpoint inhibitors, although
immune checkpoint inhibitors are superior to targeted
therapies with respect to survival. The BRAF inhibitors plus
MEK inhibitors regimen is well-tolerated, and toxicities are usually manageable and reversible, but differ according to the specific regimen used. Guidelines in the United States, Europe, and Japan recommend targeted
therapy for patients who need early
tumor responses. A meta-analysis of retrospective data shows that the baseline
lactate dehydrogenase level is significantly higher in patients treated with BRAF inhibitors plus
MEK inhibitors than in those treated with
immune checkpoint inhibitors, suggesting that clinicians tend to use BRAF inhibitors plus
MEK inhibitors for more advanced disease. Since there is insufficient efficacy and safety data on the use of targeted
therapies for acral and mucosal
melanoma, a retrospective analysis may be useful. The combination of
molecular targeted therapy plus
immune checkpoint inhibitors is expected to elicit further improvement. The results of several trials using combination or sequential
therapies will be available in the next few years.