What is the treatment protocol for Vorasidenib (investigational medication) in patients with low-grade glioma?

Vorasidenib Treatment Protocol for Low-Grade Glioma

Vorasidenib should be offered to adult patients with IDH-mutant, WHO grade 2 astrocytoma or oligodendroglioma following surgery when radiation therapy and chemotherapy can be deferred, based on high-quality evidence showing significant improvements in progression-free survival and time to next intervention. 1

Patient Selection Criteria

Tumor Characteristics Required

• IDH1 or IDH2 mutation confirmed (susceptible mutation required for FDA approval) 2
• WHO CNS grade 2 only - either oligodendroglioma (1p19q codeleted) or astrocytoma (1p19q non-codeleted) 1
• Post-surgical status: following biopsy, subtotal resection, or gross total resection 2
• Measurable non-enhancing disease (≥1 target lesion measuring ≥1 cm²) per INDIGO trial criteria, though FDA approval includes gross total resection 1
• Minimal or no contrast enhancement - any enhancement must be non-nodular and nonmeasurable 1

Clinical Eligibility

• No prior anticancer treatment for glioma (radiation or chemotherapy) 1
• Appropriate candidate for watch-and-wait approach - radiation and chemotherapy deferred or can be deferred 1
• Age ≥12 years per FDA approval (though ASCO-SNO guideline addresses adult patients only) 1, 2
• Surgery timing: INDIGO trial required 1-5 years post-surgery, but ASCO-SNO panel considers this arbitrary and reasonable to initiate at any time after postoperative recovery 1

Absolute Contraindications

• Pregnancy or breastfeeding 1
• Actively seeking pregnancy (either parent) 1
• Grade 3 or 4 glioma (outside scope of approval and evidence) 1

Dosing and Administration

Standard Dosing

• Vorasidenib 50 mg orally once daily in continuous 28-day cycles 3, 4
• Continue until disease progression or unacceptable toxicity 3

Dose-Limiting Toxicity

• Elevated transaminases occur at doses ≥100 mg and are reversible 3
• Standard dose of 50 mg once daily showed favorable safety profile 3, 4

Monitoring Protocol

Hepatic Function Surveillance

Liver function tests must be monitored rigorously due to reversible asymptomatic transaminitis as the primary grade 3+ adverse event: 1

• Every 2 weeks for the first 2 months of treatment 1
• Monthly thereafter during continued treatment 1

Radiographic Monitoring

• MRI surveillance to assess tumor response using modified RANO-LGG criteria 2
• Monitor for contrast enhancement development as marker of progression to higher grade 3

Expected Outcomes

Efficacy Data from INDIGO Trial

• Progression-free survival: Hazard ratio 0.39 (95% CI: 0.27-0.56, p<0.0001) 1, 2
  • 12-month PFS: 280 per 1,000 with vorasidenib vs 570 per 1,000 with placebo 1
• Time to next intervention: Hazard ratio 0.26 (95% CI: 0.15-0.43) 1
  • 12-month rate: 79 per 1,000 with vorasidenib vs 270 per 1,000 with placebo 1
• Median PFS in nonenhancing glioma: 36.8 months (95% CI: 11.2-40.8) in phase 1 data 3

Adverse Events

• Grade 3+ adverse events: Relative risk 1.69 (95% CI: 1.04-2.72) - primarily reversible, asymptomatic transaminitis 1
• Most common adverse reactions (≥15%): fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, seizure 2
• Treatment-related serious adverse events: 1.8% with vorasidenib vs 0.6% with placebo 1

Mechanism of Action

• Dual inhibitor of mutant IDH1 and IDH2 enzymes 3, 5
• Reduces 2-hydroxyglutarate (2-HG) production by >92% in tumor tissue 4, 5
• Brain-penetrant with demonstrated CNS activity 3, 5
• Increases DNA 5-hydroxymethylcytosine, reverses proneural/stemness gene signatures, decreases tumor cell proliferation, and activates immune cells 4

Clinical Decision-Making Algorithm

For Oligodendroglioma (IDH-mutant, 1p19q codeleted, Grade 2):

1. Post-surgery with residual/recurrent disease → Consider vorasidenib if radiation/chemotherapy deferred 1
2. Gross total resection without measurable disease → Discuss uncertain benefits of immediate vorasidenib vs observation until measurable tumor develops 1

For Astrocytoma (IDH-mutant, 1p19q non-codeleted, Grade 2):

1. Favorable prognostic factors (complete resection, younger age) → May defer radiation/chemotherapy and offer vorasidenib 1
2. Standard approach remains radiation + adjuvant chemotherapy (temozolomide or PCV) per strong recommendation 1
3. If deferral appropriate → Vorasidenib may be offered 1

Critical Caveats

FDA Approval vs Trial Criteria Discrepancies

• Gross total resection patients included in FDA approval but not INDIGO trial - benefits uncertain without measurable disease to monitor response 1
• No time restriction post-surgery in FDA approval vs 1-5 year window in INDIGO - panel considers reasonable to initiate anytime after recovery 1
• Only patients with no prior nonsurgical therapy included in trial - extrapolation to other scenarios not validated 1

Quality of Evidence Considerations

• High-quality evidence for PFS and time to next intervention 1
• Conditional (not strong) recommendation strength reflects need to balance benefits against increased adverse events and individual patient factors 1
• Overall survival data not yet mature - PFS used as appropriate endpoint given long natural history of disease 2