Ivosidenib in Isocitrate Dehydrogenase 1 - Mutated Advanced Glioma

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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02073994.

Figures

FIG 1.
FIG 1.
Clinical activity and efficacy of ivosidenib in patients with glioma. (A) Time receiving ivosidenib for the 35 patients with nonenhancing glioma. Twelve patients remain on treatment as of the data cutoff. (B) Time receiving ivosidenib for the 31 patients with enhancing glioma. Three patients remain on treatment as of the data cutoff. (C) Best response in evaluable patients with measurable disease (27 enhancing and 33 nonenhancing), expressed as the percent change in sum of products of the diameters from the target lesions at start of treatment. (D) Investigator-assessed progression-free survival according to glioma type for all evaluable patients with glioma (n = 66). Tick marks indicate censored data. PD, progressive disease; PR, partial response; SD, stable disease. (*) Lesion growth > 100%. (†) Two patients with enhancing disease had decreases of > 50% that were not confirmed and are indicated as SD.
FIG 2.
FIG 2.
(A-D) Examples of brain magnetic resonance images and manually segmented tumor volume growth curves in 4 patients with nonenhancing glioma treated with ivosidenib. IVO, ivosidenib; Tx, treatment with ivosidenib.

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