INDIGO

Background

INDIGO tested vorasidenib, a brain-penetrant dual IDH1/IDH2 inhibitor, in residual or recurrent IDH-mutant grade 2 glioma after surgery in patients not requiring immediate radiotherapy or chemotherapy (watchful-waiting population), aiming to delay progression and the need for subsequent treatment.

Interventions and follow up

Arm A: Vorasidenib 40mg PO daily
Arm B: Placebo
Primary endpoint: imaging-based PFS by blinded independent review
mFollow-up: 14.2mo

Results

n: 331 (IDH1 R132H 85%, IDH2 5%; 1p/19q-codeleted oligodendroglioma 55%)
mPFS: 27.7 vs 11.1mo (HR 0.39, 95% CI 0.27–0.56, P<.001)
24-mo PFS: 61.9% vs 30.0%
Time to next intervention: HR 0.26 (95% CI 0.15–0.43, P<.001)
OS: immature

Adverse events

Most common (any grade): fatigue, headache, COVID-19, diarrhea
Hepatic (grade ≥3): ALT elevation 9.6% vs 0% (reversible with dose modification); overall grade ≥3 AEs 22.8% vs 13.5%; one discontinuation for grade 4 ALT elevation.

Conclusions

Vorasidenib significantly extended PFS and delayed time to next intervention in IDH-mutant grade 2 glioma managed with watchful waiting, establishing targeted therapy as an option in the non-irradiated low-grade glioma setting.

Key Limitations

Surrogate imaging-based PFS endpoint; OS and long-term neurocognitive/quality-of-life outcomes immature. Selected favorable population (post-surgery, low residual burden, deferred RT/chemo); generalizability to higher-risk grade 2 disease is uncertain. Hepatotoxicity requires ongoing LFT monitoring.

Clinical Context

Based on INDIGO, the FDA approved vorasidenib (Voranigo) in August 2024 for grade 2 IDH-mutant astrocytoma or oligodendroglioma after surgery in patients ≥12 years — the first targeted systemic therapy for this disease. It offers an option to defer RT/chemotherapy and their long-term neurotoxicity; patient selection and timing relative to radiotherapy remain active questions.

References