Vorasidenib in the Treatment of Low-Grade Glioma
Vorasidenib should be offered to patients with IDH-mutant WHO grade 2 astrocytoma or oligodendroglioma after surgery when radiation and chemotherapy have been or can be deferred, as it significantly improves progression-free survival and delays the need for next intervention. 1
Patient Selection Criteria
Vorasidenib is specifically indicated for:
- Adult and pediatric patients ≥12 years old with grade 2 astrocytoma or oligodendroglioma
- Tumors must have a susceptible IDH1 or IDH2 mutation
- Patients who have undergone surgery (biopsy, subtotal resection, or gross total resection)
- Patients for whom radiation therapy and chemotherapy have been or can be deferred 1
The FDA approval in August 2024 was based on the phase III INDIGO trial, which demonstrated significant benefits in progression-free survival (PFS) with vorasidenib compared to placebo (HR: 0.39; 95% CI, 0.27-0.56) 1, 2.
Clinical Benefits
The evidence shows several important benefits:
- Improved progression-free survival: Reduced risk of disease progression by 61% compared to placebo 1
- Delayed need for next intervention: Hazard ratio of 0.26 (95% CI, 0.15-0.43), meaning patients on vorasidenib were significantly less likely to require additional treatment 1
- Sustained tumor shrinkage: Exploratory evaluations showed sustained tumor shrinkage in patients with nonenhancing glioma 3
Mechanism of Action
Vorasidenib is a first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes that:
- Reduces D-2-hydroxyglutarate (2-HG) levels in tumor tissue by >90% 4
- Shows superior brain penetrance compared to other IDH inhibitors 5
- Demonstrates ability to reverse 'proneural' and 'stemness' gene expression signatures 4
Safety Considerations
While generally well-tolerated, important safety considerations include:
- Liver function monitoring: Required every 2 weeks for the first 2 months of treatment and monthly thereafter 1
- Increased risk of adverse events: Grade 3 or higher adverse events occur more frequently with vorasidenib than placebo (22.8% vs 13.5%) 1
- Reversible transaminitis: The most common dose-limiting toxicity, occurring primarily at doses ≥100 mg 3
- Contraindications: Should not be offered to people who are pregnant, breastfeeding, or seeking pregnancy 1
Clinical Application Algorithm
Confirm eligibility:
- Histologically confirmed WHO grade 2 astrocytoma or oligodendroglioma
- Confirmed IDH1 or IDH2 mutation
- Patient has undergone surgery
- Patient is a candidate for deferral of radiation and chemotherapy
Consider tumor characteristics:
Timing considerations:
- The INDIGO trial required 1-5 years post-surgery, but the FDA approval does not include this restriction
- Treatment can be discussed at any time point after postoperative recovery 1
Monitoring during treatment:
- Regular MRI assessments to evaluate response
- Liver function tests every 2 weeks for first 2 months, then monthly
- Monitor for adverse events, particularly elevated liver enzymes
Important Caveats
- Vorasidenib is not appropriate for grade 3 or 4 gliomas, as these were not included in the INDIGO trial 1, 6
- The American Radium Society recommends that vorasidenib is "usually not appropriate" for completely resected grade 2 gliomas 6
- Vorasidenib should not be combined with radiotherapy and/or chemotherapy for any grade 2-3 glioma 6
- Long-term survival data are still pending, though median progression-free survival in patients with nonenhancing glioma was 36.8 months in early studies 3
By following this evidence-based approach, vorasidenib offers a valuable treatment option that can delay disease progression and potentially postpone the need for more toxic therapies like radiation and chemotherapy in appropriately selected patients with IDH-mutant low-grade gliomas.