Extended Follow-Up Proves Vorasidenib’s Durability in IDH-Mutant Glioma

The oral dual IDH1/2 inhibitor vorasidenib (Voranigo), approved for the treatment of IDH-mutant grade 2 astrocytoma or oligodendroglioma in patients 12 years and older, maintained clinically meaningful benefits in patients with grade 2 IDH1/2-mutant diffuse glioma following surgical resection, according to updated data from the pivotal phase 3 INDIGO trial (NCT04164901).¹

The report, newly published in The Lancet Oncology, presents the results of an additional 6 months of follow-up between the second interim analysis data cutoff on September 6, 2022, and trial unblinding on March 7, 2023.

Notable findings include a continued improvement in median progression-free survival (PFS) with vorasidenib treatment (95% CI, 22.1-not estimable [NE]) compared with placebo (11.4 months; 95% CI, 11.1-13.9), with consistent benefits observed across subgroups.² Although the median PFS with vorasidenib was NE at this point, the HR of 0.35 (95% CI, 0.25-0.49; P < .0001) indicates a 65% reduction in the risk of death with vorasidenib compared with placebo, suggesting a statistically significant and clinically meaningful benefit in this primary end point.

In terms of secondary end points, the median time to next intervention (TTNI) also favored vorasidenib treatment vs placebo (NE vs 20.1 months; HR, 0.25; 95% CI, 0.16-0.40; P < .0001), further delaying the need for subsequent therapy while prolonging survival. Additionally, a lower rate of imaging-based disease progression was observed among those treated with vorasidenib compared with those treated with placebo (32% vs 64%), along with reductions in tumor growth rate and seizure frequency.

Regarding safety, vorasidenib’s safety profile was consistent with previous reports, with no new safety signals.

"These longer-term results from the INDIGO trial build upon [vorasidenib’s] previously demonstrated clinical benefits and demonstrate reductions in tumor volume and seizure frequency in patients with IDH-mutated gliomas," said Becky Martin, PhD, chief of medical at Servier Pharmaceuticals, in a news release.¹ "One year after the FDA approval of [vorasidenib], we're immensely proud to have delivered this first-of-its-kind targeted therapy to thousands of patients living with IDH-mutated glioma, offering them clinically meaningful and durable treatment benefits supported by more than a decade of research."

Previous data presented at the 2023 American Society of Clinical Oncology Annual Meeting and simultaneously published in New England Journal of Medicine showed similar improvements in median PFS (27.7 months vs 11.1 months) and TTNI (NE vs 17.8 months; HR, 0.26; 95% CI, 0.15-0.43) among those treated with vorasidenib compared with those treated with placebo.³ These new data support the durability of benefit with vorasidenib, with minimal loss of efficacy over extended follow-up.

From Discovery to Approval: Vorasidenib’s Development Pathway

Vorasidenib, an oral, selective brain-penetrant dual inhibitor of IDH1 and IDH2 enzymes, was developed to address the dire unmet need of patients with IDH-mutant glioma who have historically grappled with the challenges of poor prognosis and limited therapeutic options. The agent’s promise in this disease has been recognized by several FDA designations throughout its development, including a fast track designation in February 2023, breakthrough therapy designation in August 2023, and priority review⁴ in February 2024 before ultimately securing FDA approval in August 2024.⁵ Two months later, the FDA approved a companion diagnostic to identify patients eligible for vorasidenib treatment.⁶

The ongoing randomized, double-blind, placebo-controlled phase 3 INDIGO trial aims to evaluate the efficacy and safety of vorasidenib vs placebo in patients with residual or recurrent grade 2 IDH1/2-mutant glioma who have received at least 1 previous surgery.⁷ Here, 331 patients have been randomly assigned 1:1 to receive either 40 mg of oral vorasidenib once daily (n = 168) or matched placebo (n = 163) in 28-day cycles.

Prior to the phase 3 trial, vorasidenib’s safety, pharmacokinetics, and preliminary efficacy were evaluated in a first-in-human phase 1 trial (NCT02481154), where the agent demonstrated favorable safety and tolerability in patients with IDH-mutant advanced solid tumors, including glioma.^8,9 Various trials are investigating the agent as maintenance therapy (phase 3 VIGOR; NCT06809322) and in combination with other agents such as temozolomide (phase 1/2; NCT06478212) and pembrolizumab (Keytruda; phase 1; NCT05484622) in IDH-mutant gliomas.

REFERENCES

1. Servier announces positive findings from longer-term analysis of the phase 3 INDIGO trial showing continued durable treatment effect of Voranigo (vorasidenib) published in The Lancet Oncology. News release. Servier Pharmaceuticals. November 3, 2025. Accessed November 3, 2025. https://tinyurl.com/3pcetf9x

2. Cloughesy TF, van den Bent MJ, Touat M, et al; INDIGO Trial Investigators. 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. Published online October 1, 2025. doi:10.1016/s1470-2045(25)00472-3

3. Mellinghoff IK, Martin, Blumenthal DT, et al; INDIGO Trial Investigators. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. 2023;389(7):589-601. doi:10.1056/nejmoa2304194

4. FDA and EMA accept vorasidenib regulatory submissions for the treatment of IDH-mutant diffuse glioma. News release. Servier. February 20, 2024. Accessed February 20, 2024. http://tinyurl.com/5bh59swj

5. FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. News release. FDA. August 6, 2024. Accessed August 6, 2024. https://tinyurl.com/3jv48wa9

6. FDA approves NGS-based companion diagnostic for first targeted therapy for patients with grade 2 IDH-mutant glioma. News release. Thermo Fisher Scientific. October 21, 2024. Accessed October 21, 2024. https://tinyurl.com/mrxhrsbd

7. 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 3, 2025. https://clinicaltrials.gov/study/NCT04164901

8. Mellinghoff IK, Penas-Prado M, Peters KB, et al. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res. 2021;27(16):4491-4499. doi:10.1158/1078-0432.ccr-21-0611

9. Study of orally administered AG-881 in patients with advanced solid tumors, including gliomas, with an IDH1 and/​or IDH2 mutation. ClinicalTrials.gov. Updated September 19, 2024. Accessed November 3, 2025. https://clinicaltrials.gov/study/NCT02481154