INDIGO: A Phase 3 Global, Randomized, Double-Blinded Study of Vorasidenib vs Placebo in Patients with Residual or Recurrent Grade 2 Glioma with an IDH1/2 Mutation

Background

• IDH1/2 mutations occur in most low-grade diffuse gliomas.
• IDH1/2 hotspot mutations occur in various cancers, including diffuse gliomas.
• IDH1/2 mutations result in:
  • Overproduction of R-2-hydroxyglutarate
  • Epigenetic dysregulation
  • Impaired cellular differentiation
  • Immunosuppressive tumor microenvironment
• Vorasidenib is an oral inhibitor of mutant IDH1 and IDH2 specifically designed for brain penetrance.
• Vorasidenib reduced tumor 2-HG by >90% in resected grade 2/3 non-enhancing diffuse glioma.

Methods

• Patients enrolled were ≥ 12 years of age with IDH1/2-mutated grade 2 oligodendroglioma or astrocytoma per WHO 2016 guidelines with prior surgery.
• Patients had measurable non-enhancing disease (≥1 target lesion measuring ≥1 cm x ≥1 cm), confirmed by blinded review.
• Patients were not in need of immediate chemotherapy or radiotherapy per investigator assessment.
• Patients were given 40 mg of vorasidenib orally once daily for 28-day cycles vs placebo.
• Centrally confirmed progressive disease permitted unblinding and crossover.
• Primary end point was progression-free survival [PFS].
• Key secondary end point was time from randomization to the initiation of first subsequent anticancer therapy or death because of any cause.

Results

• Estimated median PFS was 27.7 months for vorasidenib and 11.1 months for placebo, with a hazard ratio of 0.39.
• Time to next intervention [TTNI] was 17.8 months for placebo and wasn’t reached in the vorasidenib arm.
• At 24 months, an estimated 83.4% of patients in the vorasidenib arm had not initiated another therapy vs 27.0% of patients in the placebo arm.
• All subgroups favored vorasidenib.
• Treatment emergent adverse events:
  • Liver function tests showed increased ALT and AST present in vorasidenib arm and not in placebo.
  • Increased ALT and AST were reversible.
  • Other adverse effects were fairly even matched throughout the study.
  • No fatal treatment emergent adverse events

Conclusions

• At preplanned interim analysis, vorasidenib demonstrated a significant improvement in:
  • PFS per BIRC
    (HR 0.39, 95% CI 0.27–0.56; P=0.000000067)
  • TTNI
    (HR 0.26, 95% CI 0.15–0.43; P=0.000000019)
• Diffuse gliomas with IDH1/2 mutations are not curable with current therapies and infiltrate the brain in the absence of treatment.
• Vorasidenib is an oral inhibitor of the mutant IDH1/2 enzymes with proven brain penetrance.
• Treatment with vorasidenib significantly improved imaging-based PFS and TTNI with a manageable safety profile in patients who were not in need of immediate chemotherapy or radiotherapy​.

Mellinghoff IK, van den Bent MJ, Blumenthal DT et al. INDIGO: a Phase 3 global, randomized, double-blinded study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. Abstract presented at: 2023 ASCO Annual Meeting, June 2-6, 2023.

Funding supported by Servier Pharmaceuticals. Content independently developed by OncLive.