Recent Advances in Targeted Therapies for Adult Gliomas

Incorporation of molecular diagnostics has transformed the classification and risk stratification of adult gliomas, revealing a spectrum of therapeutically actionable targets. This review evaluates Food and Drug Administration (FDA)-approved and investigational targeted therapies and discusses the major challenges and future directions facing the field. Landmark FDA approvals, such as vorasidenib for isocitrate dehydrogenase (IDH)-mutant gliomas, dabrafenib and trametinib for BRAF V600E-mutated gliomas, neurotrophic tyrosine receptor kinase (NTRK) inhibitors for NTRK fusion-positive tumors and dordaviprone for H3K27M-mutant diffuse midline gliomas, underscore a new era of targeted therapies in neuro-oncology. These molecularly-driven therapies deliver tangible clinical benefit to select subsets of patients with molecularly defined tumors. However, they are not curative, and tumors with these targetable alterations constitute a minority of adult gliomas. Novel agents targeting DNA repair and metabolic dependencies, and leveraging immune-based and advanced strategies of drug delivery, are under investigation. Targeted therapies have begun to transform the management of molecularly defined subsets of adult glioma, though their clinical benefits remain limited to date.