Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial

Area of Science:

• Neuro-oncology
• Molecular Oncology
• Clinical Pharmacology

Background:

• Mutant isocitrate dehydrogenase (mIDH) gliomas are characterized by elevated D-2-hydroxyglutarate (2-HG).
• Vorasidenib and ivosidenib are targeted therapies inhibiting mIDH enzymes with preliminary clinical activity.
• Understanding their mechanism of action and comparative efficacy is crucial for optimizing treatment strategies.

Purpose of the Study:

• To evaluate vorasidenib and ivosidenib in a perioperative setting for recurrent low-grade glioma (LGG).
• To explore the mechanism of action of these mIDH inhibitors.
• To select a molecule for phase 3 testing based on efficacy and safety.

Main Methods:

• A phase 1 perioperative trial involving 49 patients with mIDH1-R132H nonenhancing gliomas.
• Randomized treatment arms: vorasidenib, ivosidenib, or no treatment before surgery.
• Primary endpoint: reduction in tumor 2-HG concentration; exploratory analyses of molecular and cellular changes.

Main Results:

• Significant reduction in tumor 2-HG by 92.6% with vorasidenib 50 mg q.d. and 91.1% with ivosidenib 500 mg q.d.
• Both agents were well tolerated.
• 2-HG reduction correlated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural'/'stemness' signatures, and decreased proliferation/immune activation.

Conclusions:

• Vorasidenib and ivosidenib demonstrate potent inhibition of mIDH in glioma patients.
• Vorasidenib showed superior brain penetrance and more consistent 2-HG suppression compared to ivosidenib.
• Vorasidenib was selected for phase 3 trials in mIDH LGG patients.