Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.

Abstract

PURPOSE:

Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.

PATIENTS AND METHODS:

We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.

RESULTS:

Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.

CONCLUSIONS:

Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

• Authors: Ingo K Mellinghoff, Marta Penas-Prado, Katherine B Peters, Howard A Burris 3rd, Elizabeth A Maher, Filip Janku, Gregory M Cote, Macarena I de la Fuente, Jennifer L Clarke, Benjamin M Ellingson, Saewon Chun, Robert J Young, Hua Liu, Sung Choe, Min Lu, Kha Le, Islam Hassan, Lori Steelman, Shuchi S Pandya, Timothy F Cloughesy, Patrick Y Wen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 16 Pg. 4491-4499 (08 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34078652 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Diamines
• Pyridines
• vorasidenib
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Adolescent
• Adult
• Aged
• Brain Neoplasms (drug therapy, genetics, pathology)
• Diamines (therapeutic use)
• Disease Progression
• Female
• Glioma (drug therapy, genetics, pathology)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Male
• Middle Aged
• Mutation
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Pyridines (therapeutic use)
• Young Adult