Current Treatment Paradigms for Advanced Melanoma with Brain Metastases

Melanoma brain metastases (MBM) remain a major therapeutic challenge, requiring a multidisciplinary approach integrating systemic and local therapies. The advent of immune checkpoint inhibitors and targeted therapies has markedly improved patients’ survival, with the combination of ipilimumab and nivolumab now considered as first-line systemic treatment for patients with asymptomatic MBM. Radiotherapy plays a crucial role, with stereotactic radiosurgery (SRS) now preferred over whole-brain radiotherapy (WBRT), due to its efficacy and lower risk of neurocognitive impairment. Retrospective data support a potential synergy between systemic therapy and SRS and emerging clinical evidence suggests that this combined approach may offer enhanced disease control and could become the standard of care. Key unresolved questions include the ideal sequencing of SRS with systemic treatments, the optimal radiation dose to balance efficacy and neuroprotection, and the identification of predictive biomarkers to refine patient selection. Emerging research focuses on tumor microenvironment interactions and novel radiosensitizers to enhance therapeutic outcomes. Furthermore, artificial intelligence-driven models integrating radiomics, radiogenomics, and metabolomics hold promise for advancing precision medicine in MBM management. Ongoing prospective clinical trials are crucial to establishing standardized treatment guidelines, ensuring a personalized, patient-centered approach that optimizes survival while preserving quality of life.