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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

Timothy Cloughesy, MD, reviews data from the phase 3 INDIGO trial investigating vorasidenib in patients with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation.

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    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.

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