Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; Results of a first-in-human phase I trial

Ingo K. Mellinghoff, Marta Penas-Prado, Katherine B. Peters, Howard A. Burris, 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. CloughesyPatrick Y. Wen

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4491-4499
Number of pages9
JournalClinical Cancer Research
Issue number16
StatePublished - Aug 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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