Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

Abstract

BACKGROUND:

Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.

METHODS:

In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.

RESULTS:

A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.

CONCLUSIONS:

In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

• Authors: Ingo K Mellinghoff, Martin J van den Bent, Deborah T Blumenthal, Mehdi Touat, Katherine B Peters, Jennifer Clarke, Joe Mendez, Shlomit Yust-Katz, Liam Welsh, Warren P Mason, François Ducray, Yoshie Umemura, Burt Nabors, Matthias Holdhoff, Andreas F Hottinger, Yoshiki Arakawa, Juan M Sepulveda, Wolfgang Wick, Riccardo Soffietti, James R Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth A Maher, Steven Schoenfeld, Dan Zhao, Shuchi S Pandya, Lori Steelman, Islam Hassan, Patrick Y Wen, Timothy F Cloughesy, INDIGO Trial Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 389 Issue 7 Pg. 589-601 (Aug 17 2023) ISSN: 1533-4406 [Electronic] United States
• PMID: 37272516 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2023 Massachusetts Medical Society.

Chemical References

• IDH1 protein, human
• Isocitrate Dehydrogenase
• Pyridines
• vorasidenib
• IDH2 protein, human
• Antineoplastic Agents
• Enzyme Inhibitors

Topics

• Humans
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Disease Progression
• Double-Blind Method
• Glioma (drug therapy, genetics)
• Isocitrate Dehydrogenase (genetics)
• Neoplasm Recurrence, Local (drug therapy)
• Pyridines (adverse effects)
• Antineoplastic Agents (therapeutic use)
• Enzyme Inhibitors (therapeutic use)