Included Vorasidenib Studies

This systematic review was conducted to test the hypothesis that vorasidenib, a dual inhibitor of mutant IDH1 and IDH2 enzymes, improves clinical outcomes in patients with IDH-mutant low-grade gliomas (LGGs), particularly by prolonging progression-free survival (PFS), delaying the need for chemoradiotherapy, and maintaining an acceptable safety profile. The data were derived from nine clinical trials (Phase I–III) identified through a PRISMA-guided search of six major databases up to June 2025. These studies included both early-phase single-arm trials and randomized controlled trials, with sample sizes ranging from approximately 48 to 331 patients. The populations consisted mainly of adults with histologically confirmed IDH1- or IDH2-mutant gliomas, often with residual or recurrent, non-enhancing disease. Vorasidenib was administered orally at varying doses (25–300 mg/day), with later-phase trials commonly using 40–50 mg daily, and compared against placebo or alternative IDH inhibitors such as ivosidenib. Outcomes assessed included PFS, objective response rate (ORR), time to next intervention (TTNI), reduction in the oncometabolite 2-hydroxyglutarate (2-HG), and adverse events. Risk of bias was generally low, with seven studies rated as low risk and two showing some concerns related to randomization.

The findings consistently demonstrate that vorasidenib significantly improves PFS, most notably in the Phase III INDIGO trial, where median PFS was 27.7 months compared to 11.1 months with placebo (HR 0.39, p < 0.001). Additionally, vorasidenib markedly delayed the need for further treatment, with 85.6% of patients remaining intervention-free at 18 months versus 47.4% in the placebo group. Early-phase studies showed that while objective tumor shrinkage was modest, disease stabilization occurred in up to 77.3% of patients, indicating a primarily cytostatic effect. Mechanistically, the drug demonstrated strong on-target activity, reducing intratumoral 2-HG levels by over 90%, thereby supporting its role in reversing metabolic and epigenetic dysregulation. Notably, efficacy was greater in non-enhancing tumors and in patients with higher variant allele frequency, suggesting a role for biomarker-driven treatment selection.

In terms of safety, vorasidenib was generally well tolerated, with the most common adverse events being elevated liver enzymes, headache, and nausea. Grade ≥3 adverse events occurred in approximately 20–25% of patients but were largely manageable with dose adjustments. Overall, the data suggest that vorasidenib offers a meaningful clinical benefit by delaying disease progression and postponing the need for more toxic therapies, particularly in early-stage LGG. These findings support its use as a targeted therapeutic option and highlight its potential to shift treatment paradigms toward earlier, biology-driven intervention.