Management of Brain Metastases: A Review of Novel Therapies

Brain metastases (BMs) represent the most common intracranial tumors in adults, and most commonly originate from lung, followed by breast, melanoma, kidney, and colorectal cancer. Management of BM is individualized based on the size and number of brain metastases, the extent of extracranial disease, the primary tumor subtype, neurological symptoms, and prior lines of therapy. Until recently, treatment strategies were limited to local therapies, like surgical resection and radiotherapy, the latter in the form of whole-brain radiotherapy or stereotactic radiosurgery. The next generation of local strategies includes laser interstitial thermal therapy, magnetic hyperthermic therapy, post-resection brachytherapy, and focused ultrasound. New targeted therapies and immunotherapies with documented intracranial activity have transformed clinical outcomes. Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.