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

Autor: Mellinghoff IK; Memorial Sloan Kettering Cancer Center, New York, NY, USA. MellingI@mskcc.org., Lu M; Agios Pharmaceuticals, Cambridge, MA, USA.; Mersana Therapeutics, Cambridge, MA, USA., Wen PY; Dana-Farber Cancer Institute, Boston, MA, USA., Taylor JW; University of California San Francisco, San Francisco, CA, USA., Maher EA; University of Texas Southwestern Medical Center, Dallas, TX, USA., Arrillaga-Romany I; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Peters KB; Duke University Medical Center, Durham, NC, USA., Ellingson BM; University of California, Los Angeles, Los Angeles, CA, USA., Rosenblum MK; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chun S; University of California, Los Angeles, Los Angeles, CA, USA.; California University of Science and Medicine, Colton, CA, USA., Le K; Agios Pharmaceuticals, Cambridge, MA, USA.; Aligos Therapeutics, South San Francisco, CA, USA., Tassinari A; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA., Choe S; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA., Toubouti Y; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA.; Sage Therapeutics, Cambridge, MA, USA., Schoenfeld S; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA., Pandya SS; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA., Hassan I; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA., Steelman L; Agios Pharmaceuticals, Cambridge, MA, USA.; Servier Pharmaceuticals LLC, Boston, MA, USA., Clarke JL; University of California San Francisco, San Francisco, CA, USA., Cloughesy TF; University of California, Los Angeles, Los Angeles, CA, USA.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Mar; Vol. 29 (3), pp. 615-622. Date of Electronic Publication: 2023 Feb 23.
DOI: 10.1038/s41591-022-02141-2
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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