Vorasidenib Shows Sustained Benefit in IDH-Mutant Low-Grade Glioma
Key Insights
Vorasidenib demonstrates a significant and sustained improvement in progression-free survival (PFS) compared to placebo in adults with IDH-mutant low-grade glioma (search).
The median time to next intervention (TTNI) was significantly longer with vorasidenib, indicating a durable treatment effect and delaying the need for subsequent therapies.
Updated results from a phase I study suggest vorasidenib and ivosidenib show promising activity in diffuse IDH1 (search)-mutant glioma (search), with vorasidenib demonstrating a higher response rate.
Updated results from the phase III INDIGO trial and a phase I study presented at the Society for Neuro-Oncology (SNO) meeting demonstrate the sustained efficacy and manageable safety profile of vorasidenib in patients with IDH-mutant low-grade glioma (search). The INDIGO trial's follow-up analysis showed a significant improvement in progression-free survival (PFS) and time to next intervention (TTNI) with vorasidenib compared to placebo. These findings reinforce the potential of vorasidenib as a valuable treatment option for this patient population.
INDIGO Trial: Extended Follow-Up Confirms Vorasidenib's Efficacy
The phase III INDIGO trial, involving 331 patients with IDH1 (search)/2-mutant grade 2 oligodendroglioma (search) or astrocytoma (search), compared vorasidenib to placebo. After a median follow-up of 20 months, the median PFS had not been reached in the vorasidenib arm, while it was 11.4 months in the placebo arm (P = 0.00000000013), translating to a 65% reduction in the hazard for disease progression or death. Ingo K. Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center, reported that the median TTNI was not estimable with vorasidenib versus 20.1 months for the placebo group.
Landmark analyses revealed substantial advantages for vorasidenib at 12 months (77.3% vs 47.3%) and 24 months (58.8% vs 26.7%). The PFS benefit remained consistent across all prespecified subgroups, regardless of baseline tumor volume or pretreatment tumor growth rate. The TTNI hazard ratio was 0.25, with significant advantages at 12 months (90.3% vs 74.9%) and 24 months (80.3% vs 41.4%).
Grade ≥3 treatment-emergent adverse events (TEAE) occurred more frequently with vorasidenib (26.9% vs 16.0%), particularly increased liver function tests (ALT 10.2% vs 1.2%; AST 4.8% vs 0%). Seizure incidence was similar between the groups, but on-treatment seizure events were substantially lower in the vorasidenib group (ratio of rates 0.36, P = 0.263).
Notably, tumor volume decreased by 1.3% in the vorasidenib arm, while it increased by 14.4% in the placebo group. Patients who crossed over from placebo to vorasidenib experienced a decrease in tumor volume after the switch, further highlighting the drug's efficacy.
Phase I Study: Vorasidenib and Ivosidenib in IDH1-Mutant Glioma
Long-term follow-up data from a phase I study comparing perioperative vorasidenib and ivosidenib in diffuse IDH1 (search)-mutant glioma (search) were also presented. Timothy Cloughesy, MD, of UCLA Health, reported that patients receiving vorasidenib before and after surgery, with or without radiotherapy (RT), had a median PFS of 41.4 months versus 38.3 months with ivosidenib.
The updated results showed a response rate of 45.5% with vorasidenib and 31.8% with ivosidenib. Time to response and duration of response also favored vorasidenib. In the subgroup of patients who had surgery but not RT, median PFS was 55.2 months with vorasidenib and 38.6 months with ivosidenib.
While overall safety results were similar, grade ≥3 TEAEs were more frequent in the vorasidenib group (62.5% vs 32.0%), while more patients in the ivosidenib group discontinued treatment due to TEAEs (8.0% vs 4.2%).
Both drugs reduced tumor levels of 2-hydroxyglutarate (2-HG) by more than 90%, which was associated with favorable effects on tumor growth-related factors.