Clinical trialPhase 3Brain tumours

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

The Lancet Oncology · 2025331 patients (168 in the vorasidenib group and 163 in the placebo group)

Cloughesy TF, van den Bent MJ, Touat M, Blumenthal DT, Peters KB, Ellingson BM, et al. The Lancet Oncology. 2025. 26:1665-1675

Study type: Clinical trial
Study name: INDIGO
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (1:1) at 92 hospitals in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the UK and the USA; analysis of secondary and exploratory endpoints
Sample size: 331 patients (168 in the vorasidenib group and 163 in the placebo group)
Source: The Lancet Oncology · 2025
Trial registration: NCT04164901

In plain words

Vorasidenib is a tablet that acts on changes (mutations) in the IDH1 and IDH2 genes found in some slow-growing brain tumours (grade 2 glioma). In this study, the drug slowed tumour growth and reduced the number of seizures. Quality of life, thinking and memory were no different in the drug group compared with the placebo (dummy drug) group. A rise in liver enzymes was more common in the drug group, so checking liver blood tests is important.

Key results

Median not reached (95% CI 22.1–not estimable) vs 11.4 months (11.1–13.9)

Progression-free survival (median)

Hazard ratio 0.35 (95% CI 0.25–0.49); vorasidenib vs placebo with 6 months of additional follow-up

Not estimable vs 20.1 months (17.5–27.1)

Time to next intervention

Hazard ratio 0.25 (0.16–0.40)

−1.3% (95% CI −3.2 to 0.7) with vorasidenib vs 14.4% (12.0–16.8) with placebo

Tumour growth rate

Difference 15.9% (95% CI 12.6–19.3)

Baseline: 158.2 (SD 26.4) vs 158.8 (23.3); end of treatment: 154.2 (29.8) vs 153.2 (29.4)

FACT-Br total score (mean)

Scores remained similar and high in both groups

No difference between the groups in verbal learning, executive function, attention, working memory and psychomotor function from baseline to end of treatment

Neurocognitive function

Exploratory endpoint

18.2 seizures per person-year (95% CI 8.4–39.5) vs 51.2 (22.9–114.8)

Seizure rate

Exploratory endpoint; lower rate in the vorasidenib group

Dose and schedule cards

Vorasidenib (INDIGO)

Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation, after surgery (biopsy, subtotal or gross total resection), age 12 years or older; in patients in whom radiotherapy and chemotherapy can be deferredOn the page “Brain tumours” · IDH-mutant gliomas (astrocytoma and oligodendroglioma)

Drug	Dose	Route	Schedule
Vorasidenib	40 mg once daily (children aged 12 years and older weighing less than 40 kg: 20 mg)	Oral	Continuously, with or without food

Cycle length: Continuous (28-day cycles in the trial)
Duration: Until progression or unacceptable toxicity

Hepatotoxicity: liver tests before starting, every 2 weeks for the first 2 months, then monthly for up to 2 years; depending on severity, withhold, reduce the dose or discontinue permanently. Dose reductions (adults and patients weighing 40 kg or more): 20 mg, then 10 mg daily; discontinue permanently if 10 mg is not tolerated. Avoid concomitant strong and moderate CYP1A2 inhibitors, moderate CYP1A2 inducers and smoking; non-hormonal contraception is required. Swallow tablets whole; take a missed dose only if no more than 6 hours have passed. Grade 3 or higher ALT elevation occurred in 9.6% of patients.

On the page “Brain tumours” · IDH-mutant gliomas (astrocytoma and oligodendroglioma)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Vorasidenib group

Oral vorasidenib 40 mg once daily in continuous 28-day cycles until disease progression or intolerable toxicity (168 patients).

2Placebo group

Oral placebo once daily in continuous 28-day cycles until disease progression or intolerable toxicity (163 patients).

Source of the regimen details: Abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 12 years or older with IDH1/2-mutant grade 2 diffuse glioma who had residual or recurrent tumour, a Karnofsky performance score of 80 or higher, at least one previous surgery and no other anticancer treatment. Randomisation was stratified by 1p/19q co-deletion status (determined locally) and baseline tumour size.

Endpoints

Primary endpoint: progression-free survival (PFS) by blinded independent review committee. Key secondary endpoint: time to next intervention. Prespecified secondary endpoints: tumour growth rate (six-monthly change in tumour volume) and health-related quality of life (FACT-Br). Prespecified exploratory endpoints: neurocognitive function (cognitive performance instruments) and seizure activity (patient-reported).

Safety and side effects

The most common grade 3 or worse treatment-emergent adverse events in the vorasidenib and placebo groups, respectively, were increased alanine aminotransferase (17 patients [10%] versus 2 patients [1%]), increased aspartate aminotransferase (8 patients [5%] versus none), seizure (7 patients [4%] versus 5 patients [3%]) and increased gamma-glutamyltransferase (5 patients [3%] versus 2 patients [1%]). Serious treatment-emergent adverse events occurred in 20 patients (12%) in the vorasidenib group and 10 patients (6%) in the placebo group, the most common being seizure. No treatment-related deaths were reported.

Clinical significance and place in guidelines

This analysis shows that the superiority of vorasidenib in progression-free survival and time to next intervention is confirmed with 6 months of additional double-blind follow-up. A benefit in reducing tumour growth and controlling seizures was also seen, with no negative effect on quality of life or neurocognitive function. According to the authors, these findings support the use of vorasidenib in patients with IDH1/2-mutant grade 2 glioma who have had surgery only and do not need immediate radiotherapy or chemotherapy. The status of drug approvals and guideline recommendations should be checked separately, as the abstract does not mention them.

Limitations

The results concern secondary and exploratory endpoints, and the exploratory endpoints (neurocognitive function and seizures) were not designed to confirm hypotheses. Seizure activity was patient-reported and the confidence intervals for seizure rates are wide. Median follow-up was about 20 months and the trial is ongoing. The study was funded by Servier and several authors are its employees. Most patients were White (78%). Overall survival data are not reported in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.