Challenges and perspectives in the management of BRAF-mutated metastatic melanoma: Systemic treatment sequencing and brain metastases

Abstract

The global incidence of metastatic melanoma with BRAF mutations, characterized by aggressive behavior and poor prognosis, is rising. Recent treatment advances, including immune checkpoint inhibitors (ICI) and targeted therapies (TT) such as BRAF and MEK inhibitors, have significantly enhanced patient outcomes. Although guidelines recommend sequencing strategies, real-world implementation can be influenced by clinical scenarios. This article highlights the importance of tailored treatment strategies, emphasizing that the decision to initiate immunotherapy (IT) or TT hinges on multiple factors, including tumor burden, LDH levels, presence of brain metastases, and patient symptomatic status. Managing brain metastases also poses a challenge, as these patients are typically excluded from pivotal clinical trials. While insights from phase II studies provide some guidance, there is a critical need for more quality data to inform comprehensive recommendations. Furthermore, although triple therapy combining IT and TT was initially thought to be promising, it has failed to clearly demonstrate benefit over current treatments. For all these reasons, there is an imperative need for further research on biomarkers and predictive factors, as well as real-world studies, that will help tailor treatment strategies across diverse patient subsets, thereby refining therapeutic approaches for BRAF-mutated metastatic melanoma.