Brain metastasis: Opportunities for novel therapies

Brain metastases (BM) are a common and clinically significant manifestation of advanced cancer that increasingly influences treatment decisions across solid tumors. Management requires a tailored approach because intracranial disease may behave differently from extracranial disease, reflecting differences in drug penetration, blood-brain barrier biology, and the local immune milieu. This review summarizes the current biologic and clinical framework of BM, including molecular divergence from the primary tumor, the evolution of prognostic models, and the growing role of brain-specific risk stratification in treatment planning. It also reviews contemporary evidence for systemic therapies with intracranial activity across major tumor types, with particularly important advances in oncogene-driven non-small cell lung cancer, human epidermal growth factor receptor 2-positive breast cancer, melanoma, and renal cell carcinoma. In addition, the review examines the integration of systemic therapy with local approaches such as stereotactic radiosurgery, where safety appears to be more agent-specific than timing-specific. Emerging strategies, including focused ultrasound-mediated blood-brain barrier opening and tumor treating fields, may further broaden therapeutic possibilities. The management of BM increasingly depends on a multidisciplinary, biologically informed approach supported by more consistent intracranial endpoints and dedicated central nervous system-focused research.