Vorasidenib Sustains Lower Seizure Rates in Grade 2 IDH-Mutant Glioma In INDIGO Follow-Up

Vorasidenib (Voranigo) sustained lower seizure rates compared with placebo over longer follow-up in patients with grade 2 IDH-mutant glioma, an effect driven by patients with oligodendroglioma, according to findings from an exploratory analysis of the phase 3 INDIGO trial (NCT04164901) presented at the 2026 SNO Annual Meeting.¹

At the January 17, 2025, data cutoff, among patients who had experienced at least 1 seizure at baseline or during treatment, the rate of seizures per person-year with vorasidenib (n = 56) was 15.9% (95% CI, 9.1%-27.1%), translating to a ratio of rates of 0.28 vs placebo (95% CI, 0.14-0.55; P = .0002). In patients with oligodendroglioma (n = 29), the seizure rate with vorasidenib was 6.9% per person-year (95% CI, 2.7%-17.7%), and the ratio of rates was 0.09 (95% CI, 0.04-0.22; P < .0001). In patients with astrocytoma (n = 27), this rate was 17.5% per person-year (95% CI, 9.4%-32.3%), and the ratio was 0.83 (95% CI, 0.38-1.82; P = .6448). The analyses were exploratory, were not prespecified, and were not adjusted for multiplicity. Data from patients in the placebo arm who crossed over to receive vorasidenib were excluded.

“The main effect is driven by the oligodendroglioma tumors, where the rate of seizures in the placebo-treated patients was a lot higher compared [with that in] the vorasidenib-treated patients,” Wolfgang Wick, MD, chairman of the German Science and Humanities Council, medical director of General Neurology, a chair in neurology, and center spokesman for the Head Clinic at Heidelberg University Hospital, as well as department head for neuro-oncology at the German Cancer Research Center in Germany, stated in a presentation of the data. “In the placebo-treated patients with oligodendroglioma, the incidence of seizures is going up, whereas the incidence of seizures in the other patients is remaining low or is decreasing over time, which is an important clinical finding.”

What was the design of the phase 3 INDIGO trial of vorasidenib in grade 2 IDH-mutant glioma?

The trial enrolled patients ages 12 years and older whose grade 2 oligodendroglioma or astrocytoma carried an IDH1 or IDH2 mutation.^1,2 Patients needed to have disease that recurred or persisted after surgery alone and did not yet warrant chemotherapy or radiotherapy. The primary end point was progression-free survival as judged by a blinded independent review committee. Patients were ineligible for enrollment if their seizures remained uncontrolled, defined as persistent seizures that disrupted daily activities despite 3 antiseizure regimens, including at least 1 combination.¹ From January 2020 to February 2022, 331 patients were randomly assigned 1:1 to receive vorasidenib at 40 mg (n = 168) or placebo (n = 163), each taken orally once daily in 28-day cycles. Patients receiving placebo were allowed to switch to receive vorasidenib once progression was confirmed or the trial was unblinded.

The current analysis used the January 17, 2025, data cutoff, when the median follow-up was 41.6 months, and the median progression-free survival (PFS) with vorasidenib was 44.1 months.

What did earlier INDIGO results show with vorasidenib in grade 2 IDH-mutant glioma?

Vorasidenib, a brain-penetrant oral inhibitor of mutant IDH1 and IDH2, has been approved in more than 40 countries, including the United States, for the treatment of patients 12 years and older with grade 2 IDH-mutant diffuse glioma.^1,3 In the primary analysis, published in 2023, the median PFS was 27.7 months (95% CI, 17.0-not estimated) with vorasidenib vs 11.1 months (95% CI, 11.0-13.7) with placebo (HR, 0.39; 95% CI, 0.27-0.56; P < .001) at a median follow-up of 14.2 months, and the time to next intervention favored vorasidenib (HR, 0.26; 95% CI, 0.15-0.43; P < .001).⁴ A secondary and exploratory analysis at the March 7, 2023, unblinding cutoff, published in 2025, reported a seizures-per-person-year rate of 18.2% (95% CI, 8.4%-39.5%) with vorasidenib.^1,5 At that cutoff, the ratio of rates was 0.36 (95% CI, 0.14-0.89; P = .0263) overall, 0.14 (95% CI, 0.05-0.42; P = .0005) in patients with oligodendroglioma, and 0.91 (95% CI, 0.39-2.11; P = .8266) in those with astrocytoma.

What did longer INDIGO follow-up show for quality of life and tumor progression in IDH-mutant glioma?

In the current analysis, the HR for time to worsening on the Functional Assessment of Cancer Therapy–Brain was 0.72 (95% CI, 0.39-1.34; P = .2937) in the overall population and 0.38 (95% CI, 0.15-1.00; P = .0435) in patients with a history of at least 1 seizure (n = 56 per arm).¹ On the brain cancer subscale, the HR was 0.55 (95% CI, 0.29-1.06; P = .0699) overall and 0.32 (95% CI, 0.11-0.91; P = .0263) in patients who had experienced at least 1 seizure.

Seizure burden tracked with tumor burden. In the overall population (n = 307), a larger baseline tumor size was associated with a higher seizure number (coefficient, 0.5; standard error, 0.20; P = .010). Seizure rates were higher after radiographic progression (n = 160) than during progression-free periods (n = 327), with a ratio of rates of 3.74 (95% CI, 1.69-8.28). These correlation and progression analyses were not prespecified and were not adjusted for multiplicity.

What do the INDIGO findings mean for seizure control with vorasidenib in IDH-mutant glioma?

Wick reported that vorasidenib produced durable seizure control, that quality of life remained intact even among patients with active seizures, and that progression and a larger tumor were tied to more seizures, supporting a longer progression-free period.

However, he cautioned about how vorasidenib should be viewed in this context, saying, “[vorasidenib] is not an anticonvulsant and should not be treated as an anticonvulsant, so patients are in need of anticonvulsive therapy in addition to vorasidenib. On the other hand, [these results on the decreased number of seizures] may be a result of a sustained and, over time, increasing impact [of vorasidenib] on the volume of the disease.”

Disclosures: Wick reported receiving grant or research support from Apogenix, Pfizer, and Roche; as well as receiving consulting fees from AstraZeneca and Roche.

References

1. Wick W, Mellinghoff IK, van den Bent MJ, et al. Impact of vorasidenib vs placebo on seizure rates and quality of life: exploratory analysis from phase 3 INDIGO study. Presented at: 2026 SNO Annual Meeting; November 12-15, 2026; Philadelphia, PA. Abstract CTNI-34.
2. Study of vorasidenib (AG-881) in participants with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation (INDIGO). ClinicalTrials.gov. Updated April 3, 2025. Accessed November 15, 2026. https://clinicaltrials.gov/study/NCT04164901
3. FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. FDA. August 6, 2024. Accessed November 15, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation
4. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. 2023;389(7):589-601. doi:10.1056/NEJMoa2304194
5. Cloughesy TF, van den Bent MJ, Touat M, et al. Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2025;26(12):1665-1675. doi:10.1016/S1470-2045(25)00472-3