Vorasidenib for Grade 2 IDH-Mutant Glioma Improves Progression-Free Survival

Vorasidenib, a brain-penetrant inhibitor of mutant enzymes, significantly improved progression-free survival (PFS) and delayed time to the next intervention in patients with grade 2 isocitrate dehydrogenase (IDH)-mutant glioma. These are the findings of a study published in The New England Journal of Medicine.

Grade 2 IDH-mutant glioma grows slowly and continuously and eventually becomes an aggressive tumor infiltrating normal brain tissue. Standard of care for the subset of patients at high risk for early disease progression is radiation therapy plus chemotherapy. Optimally this regimen can result in long-lasting disease remission but is not a curative solution and is associated with toxic effects.

Given the need for more effective and safer treatments, researchers conducted an international, double-blind, randomized, placebo-controlled, phase 3 trial, Investigating Vorasidenib in Glioma (INDIGO; ClinicalTrials.gov Identifier: NCT04164901), to evaluate the safety and efficacy of vorasidenib, a dual IDH1 and IDH2 inhibitor.

The researchers recruited patients (N=331) with residual or recurrent grade 2 IDH-mutant oligodendroglioma or astrocytoma at 77 sites in 10 countries between 2020 and 2022 and randomly assigned them in a 1:1 ratio to receive 40 mg oral vorasidenib (n=168) or placebo (n=163) daily in 28-day cycles.

The primary outcome of this prespecified interim analysis was imaging-based PFS, defined as time from randomization to first documented progression or death from any cause.

The intervention and control cohorts comprised:

• 60.1% and 52.8% men, aged median 40.5 (range, 21-71) and 39 (range, 16-65) years,
• 52.4% and 51.5% had oligodendroglioma,
• 63.7% and 70.6% had frontal tumors at diagnosis,
• 97.0% and 93.3% were IDH1-positive,
• 86.9% and 84.7% were IDH2-positive, and
• 25.0% and 17.8% had undergone 2 or more previous surgeries, respectively.

Median PFS was 27.7 months among the patients who took vorasidenib compared with 11.1 months among control individuals, indicating significant improvement in PFS over placebo (hazard ratio [HR], 0.39; 95% CI, 0.27-0.56; P <.001).

In the subgroup analyses, vorasidenib was significantly favored or tended to be favored over placebo for prolonging PFS among all groups.

In addition, the time to next intervention was not reached among the intervention cohort compared with 17.8 months among control individuals, indicating a significant prolongation of time-to-next treatment (HR, 0.26; 95% CI, 0.15-0.43; P <.001). As in the main subgroup analysis, vorasidenib at least tended to be favored over placebo in all subgroups for prolonging the time to next intervention.

Any grade adverse event (AE) occurred among 94.6% and 93.3% and grade 3 or higher events among 22.8% and 13.5% of the vorasidenib and placebo cohorts, respectively. Among the vorasidenib group, the most common grade 3 or higher events were increased alanine aminotransferase (9.6%), increased aspartate aminotransferase (4.2%), and seizure (4.2%).

AEs leading to discontinuation occurred among 3.6% and 1.2%, leading to a dose reduction among 10.8% and 3.1%, and leading to interruption among 29.9% and 22.7% of the vorasidenib and placebo groups, respectively.

This study may be limited by the small sample sizes in some subgroups.

The results of this study supported the use vorasidenib for prolonging PFS and time to next intervention with a tolerable safety profile among patients with grade 2 IDH-mutated gliomas.

The researchers wrote, “[T]reatment with vorasidenib significantly improved both imaging-based progression-free survival according to blinded independent review and the time to the next intervention, as compared with placebo, among patients who were considered to be candidates for a watch and- wait approach.”

“[T]he findings of this trial could be generalized to the real-world setting regarding how these patients are treated,” they concluded.

Disclosures: This research was supported by Servier. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.