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Open Access Publications from the University of California

Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma.

  • Author(s): Mellinghoff, Ingo K
  • Ellingson, Benjamin M
  • Touat, Mehdi
  • Maher, Elizabeth
  • De La Fuente, Macarena I
  • Holdhoff, Matthias
  • Cote, Gregory M
  • Burris, Howard
  • Janku, Filip
  • Young, Robert J
  • Huang, Raymond
  • Jiang, Liewen
  • Choe, Sung
  • Fan, Bin
  • Yen, Katharine
  • Lu, Min
  • Bowden, Chris
  • Steelman, Lori
  • Pandya, Shuchi S
  • Cloughesy, Timothy F
  • Wen, Patrick Y
  • et al.

PURPOSE:Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS:We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with mIDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS:In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION:In patients with mIDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

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