Vorasidenib Sustains Clinical Benefit in IDH1/2-Mutant Glioma: Longer-Term Results From the INDIGO Trial

Longer-term results from the ongoing phase 3 INDIGO trial show vorasidenib, an oral brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), continues to demonstrate clinical benefit and reductions in tumor volume and seizure frequency among patients with grade 2 IDH1/2-mutant diffuse glioma.

As previously shown, “vorasidenib improved progression-free survival and time to next intervention at the second interim analysis, resulting in study unblinding,” stated Timothy Cloughesy, MD, University of California, Los Angeles, California, and coauthors. “Here, researchers report 6 months of additional double-blind data, from the second interim analysis to unblinding.”

In this double-blind, placebo-controlled trial, researchers enrolled 331 patients 12 years of age and older with a Karnofsky performance-status score of ≥80 who had undergone at least 1 previous surgery and received no prior anticancer therapy. Patients were randomized 1:1 to receive either 40 mg of vorasidenib (n = 168) or placebo (n = 163) in continuous 28-day cycles until disease progression or unacceptable toxicity, stratified by locally determined chromosome 1p/19q codeletion status and baseline tumor size. 

The primary end point was progression-free survival (PFS). Key secondary and exploratory end points included time to next intervention, tumor growth rate, health-related quality of life (assessed via the Functional Assessment of Cancer Therapy–Brain [FACT-Br] score), neurocognitive function, seizure control, and safety.

At a median follow-up of 20.1 months, median PFS was not reached in the vorasidenib arm and was 11.4 months in the placebo arm. Time to next intervention was not reached in the vorasidenib arm and was 20.1 months in the placebo arm. The mean difference in tumor growth rate was 15.9%, with rates of -1.3% in the vorasidenib arm and 14.4% in the placebo arm. Mean baseline FACT-Br scores were 158.2 in the vorasidenib arm and 158.8 in the placebo arm and 154.2 and 153.2, respectively at the end of treatment. 

There were no differences reported in neurocognitive domains including verbal learning, executive function, attention, working memory, and psychomotor function from baseline through the end of treatment. Notably, seizure rates were 18.2 seizures per person per year in the vorasidenib arm and 51.2 seizures per person per year in the placebo arm.

The most common grade ≥3 treatment-emergent adverse events included increased alanine aminotransferase, increased aspartate aminotransferase, seizure, and increased γ-glutamyltransferase. Serious treatment-related adverse events occurred in 12% and 6% of patients in the vorasidenib and placebo arms, respectively. No treatment-related deaths were reported.

“Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma,” concluded Dr Cloughesy et al. “These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who have undergone surgical intervention and are not in immediate need of radiotherapy or chemotherapy.”

Source: 

Cloughesy TF, van den Bent M, Touat M, et al. Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): Secondary and exploratory endpoints from a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. Published online: Ocotber 29, 2025. doi:10.1016/S1470-2045(25)00472-3