Randomized phase 1 trial of perioperative vorasidenib or ivosidenib in IDH1-mutant low-grade glioma

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. A multicenter phase 1 trial in the United States randomized patients with mIDH1-R132H nonenhancing recurrent low-grade glioma to vorasidenib or ivosidenib or no treatment before surgery, with the option of receiving postpostoperative treatment until disease progression or unacceptable toxicity. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG) in tumor tissue, the metabolic product of mIDH enzymes. Tumor 2-HG concentrations were reduced by 92.6% (95% CrI 76.1-97.6) and 91.1% (72.0-97.0) in patients treated with vorasidenib and ivosidenib, respectively. Both agents were well tolerated. Reduction of 2-HG was associated with decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppresion than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGG.