As reported in The New England Journal of Medicine by Ingo K. Mellinghoff, MD, FACP, and colleagues, the phase III INDIGO trial has shown that vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, significantly improved progression-free survival vs placebo in patients with IDH1- or IDH2-mutant residual or recurrent grade 2 glioma who had received no prior treatment other than surgery.

Ingo K. Mellinghoff, MD, FACP

Study Details

In the double-blind trial, 331 patients from sites in 10 countries were randomly assigned between January 2020 and February 2022 to receive vorasidenib at 40 mg once daily (n = 168) or placebo (n = 163) in 28-day cycles. The primary endpoint was imaging-based progression-free survival on blinded assessment by independent review committee. Crossover to vorasidenib from placebo was permitted upon disease progression.

Progression-Free Survival

Median follow-up was 14.0 months (interquartile range [IQR] = 10.1–17.9 months) in the vorasidenib group and 14.3 months (IQR = 10.0–18.1 months) in the placebo group. Median progression-free survival was 27.7 months (95% confidence interval [CI] = 17.0 months to not estimable) in the vorasidenib group vs 11.1 months (95% CI =11.0–13.7 months) in the placebo group (hazard ratio [HR] = 0.39, 95% CI = 0.27–0.56, P < .001).

Overall, 19 patients (11.3%) in the vorasidenib group received another anticancer therapy, including surgery, chemotherapy, and radiation therapy. A total of 58 (35.6%) in the placebo group received another anticancer intervention, including crossover to vorasidenib (n = 52, 31.9%), surgery, chemotherapy, and radiation therapy. Median time to next cancer intervention, a key secondary endpoint, was not reached in the vorasidenib group and was 17.8 months in the placebo group (HR = 0.26, 95% CI = 0.15–0.43, P < .001).   

The proportions of patients remaining alive without receiving a subsequent treatment intervention was 85.6% (95% CI = 77.8%–90.8%) in the vorasidenib group vs 47.4% (95% CI = 35.8%–58.2%) in the placebo group at 18 months and 83.4% (95% CI = 74.0%–89.6%) vs 27.0% (95% CI = 7.9%–50.8%) at 24 months.

Adverse Events

The most common adverse events of any grade in the vorasidenib group were increased alanine aminotransferase (38.9%), COVID-19 infection (32.9%), and fatigue (32.3%). Grade ≥ 3 adverse events occurred in 22.8% of patients in the vorasidenib group vs 13.5% of the placebo group. The most common adverse event in the vorasidenib group was increased alanine aminotransferase (9.6% vs 0% in placebo group); other events more common in the vorasidenib group were increased aspartate aminotransferase (4.2% vs 0%) and increased γ-glutamyltransferase (3.0% vs 1.2%). Serious adverse events considered related to treatment occurred in 1.8% vs 0% of patients. Adverse events led to the discontinuation of vorasidenib in 3.6% and placebo in 1.2% of patients.

The investigators concluded, “In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention.”

Dr. Mellinghoff, of the Department of Neurology, Memorial Sloan Kettering Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Servier. For full disclosures of the study authors, visit nejm.org.