Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumours that cause considerable disability and premature death. Vorasidenib is an investigational drug that crosses the blood-brain barrier and inhibits mutated IDH1 and IDH2. Recently published in The New England Journal of Medicine, the results of the INDIGO trial showed that vorasidenib significantly improves progression-free survival and delays the time to the next intervention in patients with residual or recurrent grade 2 IDH-mutant glioma.
Gliomas are the most common malignant primary brain tumour type in adults. Most grade 2 gliomas have mutations in the metabolic enzymes isocitrate dehydrogenases (IDH) 1 or 2. Vorasidenib is an investigational drug that crosses the blood-brain barrier and inhibits mutated IDH1 and IDH2. The phase 3 INDIGO trial evaluated whether vorasidenib, when administered at an oral daily dose of 40 mg, would improve progression-free survival and delay the initiation of further anticancer therapy in patients with residual or recurrent IDH-mutant grade 2 gliomas who had undergone surgery as their only previous treatment.
The double-blind, phase 3 INDIGO trial included patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery. In total, 331 patients were randomly assigned to receive oral vorasidenib, 40 mg once daily (n=168) or matched placebo (n=163) in 28-day cycles. The primary endpoint was imaging-based progression-free survival (PFS). The key secondary endpoint was the time to the next anticancer treatment. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression.
After a median follow-up of 14.2 months, PFS was significantly longer in the vorasidenib group as compared with the placebo group (27.7 vs. 11.1 months, respectively; HR[95%CI]: 0.39[0.27-0.56]; p<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (HR[95%CI]: 0.26[0.15-0.43]; p<0.001). The probability of not receiving a next treatment after 24 months was 83% in the vorasidenib group vs. 27% in the placebo group. Adverse events (AE) of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and 13.5% of those who received placebo. The most common grade ≥3 AEs were increased alanine aminotransferase (9.6% vs. 0% in the vorasidenib and placebo groups, respectively), aspartate aminotransferase (4.2% vs. 0%) and gamma-glutamyltransferase (3.0% vs. 1.2%) levels.
In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved PFS and delayed the time to the next intervention, compared to placebo. Additionally, vorasidenib had a safety profile of mainly low-grade toxic effects. Adverse events of grade ≥ 3 were more common in the vorasidenib group than in the placebo group, although the incidence of serious adverse events and discontinuations of vorasidenib or placebo were low.