Update on the treatment of <i>BRAF</i>mut metastatic melanoma and future perspectives

Abstract v‐Raf murine sarcoma viral oncogene homolog B ( BRAF ) mutations were first identified in melanoma in 2002, leading to increased cell division and proliferation, and resultant tumour growth. The identification and characterisation of BRAF mutations ( BRAF mut) led to the development of several highly specific, BRAF‐, then mitogen‐activated kinase enzyme (MEK)‐targeted therapies that have enabled rapid tumour responses and improved treatment outcomes in most patients with metastatic BRAF mut melanoma. The combination of these two drug classes (BRAF inhibitors and MEK inhibitors) has demonstrated improved response rates, progression‐free survival, and overall survival (OS), along with a more tolerable safety profile, compared with BRAF inhibition alone. In parallel, improved knowledge of the immune system has enabled the development of immune checkpoint inhibitors (ICIs), although immune‐related adverse events with ICIs may prove to be problematic in some patients and require careful management. While targeted therapy appears to provide rapid disease control in a relatively high proportion of patients, the development of secondary resistance may limit the overall duration of responses. Acquired resistance, along with primary resistance, has also been reported for ICIs, with a lower overall response rate to that with targeted therapy, although durable responses have been reported in some responding patients. A combination strategy of targeted therapy with ICIs has demonstrated modest increases in efficacy compared with targeted therapy combinations, although data significance varies across studies, there is increased risk of toxicity, and triple combination therapy has not yet received clinical approval in Europe. Thus, there is an ongoing need to establish optimal sequencing of these treatments in patients with advanced BRAF mut melanoma, and this has become the focus of current research. The aim of this narrative review was to provide an update on the treatment of BRAF mut metastatic melanoma, current guideline recommendations, and future clinical perspectives.