Evolving treatment paradigms for melanoma brain metastases: A systematic review of current modalities

Abstract

Background: Melanoma brain metastases (MBM) affect up to 60 % of advanced melanoma cases and are associated with poor prognosis and significant neurologic morbidity. Recent advancements include immune checkpoint inhibitors (ICIs), BRAF/MEK-targeted inhibitors, stereotactic radiosurgery (SRS), and combination strategies, but optimal integration of these modalities remains unclear.

Methods: We conducted a systematic review of studies published from 2009 to 2024 across PubMed, Scopus, and Web of Science. Included studies reported outcomes such as overall survival (OS), progression-free survival (PFS), intracranial response rate (IRR), and adverse events (AEs) in patients receiving systemic therapies, radiotherapy, surgery, or combination regimens. Risk of bias was assessed using the Cochrane, Newcastle-Ottawa, and Joanna Briggs Institute (JBI) tools.

Results: 70 studies met inclusion criteria. ICIs demonstrated durable responses, especially in asymptomatic patients not requiring corticosteroids. Nivolumab and pembrolizumab offered superior response rates and OS versus chemotherapy. Targeted therapies like dabrafenib and vemurafenib produced rapid intracranial control but less durable responses. SRS improved local control with low neurotoxicity and showed synergy when combined with ICIs. Triple-modality strategies (surgery+SRS+systemic therapy) showed the most promising survival outcomes in selected patients. Median OS (mOS) ranged from 5.3 to 15.9 months, depending on treatment and patient selection.

Conclusion: Management of MBM is shifting toward multimodal approaches integrating local and systemic therapies. ICIs, particularly when paired with SRS, remain central to treatment. Prospective, biomarker-driven studies are needed to clarify treatment sequencing, maximize intracranial control, and improve quality of life (QoL).

Keywords: BRAF/MEK inhibitors; Combination therapy; Immune checkpoint inhibitors; Intracranial disease control; Melanoma brain metastases; Multimodal treatment; Overall survival; Progression-free survival; Stereotactic radiosurgery; Systemic therapy.