Targeting Mutant IDH in Glioma: Mechanistic Insights and Clinical Implications of Vorasidenib

<ns5:p>Gliomas account for approximately 25–29% of intracranial tumors and up to 80% of malignant brain tumors, with low-grade gliomas (LGGs) predominantly affecting younger individuals. Conventional treatments, including surgery, radiotherapy, and chemotherapy, provide disease control but are limited by neurotoxicity and long-term adverse effects, highlighting the need for targeted therapies. This systematic review evaluates the efficacy and safety of vorasidenib, a dual isocitrate dehydrogenase (IDH) 1/2 inhibitor, in patients with IDH-mutant gliomas, focusing on progression-free survival (PFS), overall survival (OS), and safety outcomes. Following PRISMA guidelines, six databases (PubMed, Cochrane, Wiley, Epistemonikos, EBSCO, and Google Scholar) were searched up to June 2025. Eligible studies included clinical trials involving patients with histologically confirmed IDH1- or IDH2-mutant gliomas. Data extracted included study design, patient characteristics, treatment regimens, efficacy endpoints, and safety profiles. Risk of bias was assessed using the Cochrane RoB 2 tool. Of 1,426 records identified, nine studies met the inclusion criteria. Vorasidenib significantly improved PFS compared with placebo in the Phase III INDIGO trial (median PFS 27.7 vs 11.1 months; HR 0.39, p < 0.001) and delayed the need for chemoradiotherapy. Phase I trials reported disease stabilization in up to 77.3% of patients and a > 90% reduction in intratumoral 2-hydroxyglutarate. The most frequent adverse events were hepatic enzyme elevations, with grade ≥ 3 events occurring in approximately 20–25% of patients. Vorasidenib shows meaningful clinical benefit and a manageable safety profile, supporting its role as a promising targeted therapy for IDH-mutant LGGs.</ns5:p>