Vorasidenib and
ivosidenib inhibit mutant forms of
isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH
glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade
glioma (
IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of
D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH
enzymes, measured in
tumor tissue from 49 patients with mIDH1-R132H nonenhancing
gliomas following randomized treatment with
vorasidenib (50 mg or 10 mg once daily, q.d.),
ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery.
Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with
vorasidenib 50 mg q.d. and
ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased
DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased
tumor cell proliferation and immune cell activation.
Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than
ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios
Pharmaceuticals, Inc. and Servier
Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.