Current and emerging strategies for the management of brain and leptomeningeal metastases in melanoma.

Melanoma exhibits a marked predilection for central nervous system (CNS) dissemination, including both brain parenchymal metastases and leptomeningeal metastases (LMM), which together represent a major cause of morbidity and mortality. Historically characterized by poor prognosis, CNS melanoma has undergone a paradigm shift in management over the last decade with the advent of immune checkpoint inhibitors and targeted therapies, as well as advances in local treatment modalities such as stereotactic radiosurgery. While outcomes for patients with melanoma brain metastases have significantly improved, leptomeningeal melanoma metastases remain a devastating condition with limited evidence-based therapeutic options. This review provides a comprehensive and up-to-date overview of the epidemiology, biological determinants, diagnostic strategies, and therapeutic management of melanoma with cerebral and leptomeningeal involvement. Particular emphasis is placed on systemic treatment strategies, including immune checkpoint inhibitors, BRAF/MEK-targeted therapies, and their integration with local treatments. Dedicated attention is given to leptomeningeal disease, highlighting emerging data on systemic immunotherapy, intrathecal approaches, and innovative therapeutic strategies aimed at overcoming the blood-brain and blood-CSF barriers. Finally, we address current challenges, unmet clinical needs, and future perspectives, including biomarker development, novel agents, and rational combination strategies, with the goal of improving outcomes for this high-risk population.