Ivosidenib, an inhibitor of mutant IDH1, was safe and showed early evidence of efficacy in glioma.

  • Major Finding: Ivosidenib, an inhibitor of mutant IDH1, was safe and showed early evidence of efficacy in glioma.

  • Concept: In this phase I trial, patients with MRI-nonenhancing tumors fared best; most had stable disease.

  • Impact: This work supports further investigation of inhibitors of mutant IDH in IDH1-mutant glioma.


The majority of lower-grade (WHO grades 2 and 3) gliomas harbor mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1), and these mutations contribute to tumorigenesis. Mellinghoff, Ellingson, Cloughesy, and colleagues conducted a phase I trial of the first-in-class oral IDH1 inhibitor ivosidenib—already approved by the FDA for the treatment of IDH1-mutant leukemia—in 66 patients with IDH1-mutant gliomas ranging in grade from 2 to 4. Two thirds of patients had received prior radiation or systemic cancer therapy. Ivosidenib was generally well tolerated, with no dose-limiting toxicities observed and no patients discontinuing treatment due to adverse events. Adverse events grade three or higher occurred in 19.7% of patients but were considered to be related to treatment in only 3% of cases. With regard to treatment efficacy, patients with MRI-nonenhancing (generally considered less advanced) gliomas fared better than those with MRI-enhancing (generally considered more advanced) disease. One patient (1.5%) with MRI-nonenhancing glioma exhibited a partial response, and 85.7% of patients with MRI-nonenhancing tumors experienced stable disease. In contrast, no patients with MRI-enhancing gliomas had a response, and 45.2% of patients in this group had stable disease. Progression-free survival (PFS) data also highlighted the disparities between the two groups, with median PFS being 13.6 months in patients with MRI-nonenhancing tumors versus 1.4 months in those with MRI-enhancing tumors. The finding that patients with MRI-nonenhancing tumors appeared to have better responses to ivosidenib was unexpected because drug delivery to MRI-nonenhancing tumors is often less effective than delivery to MRI-enhancing tumors. However, because MRI-nonenhancing tumors are less advanced, they may have fewer treatment-inhibiting genetic aberrations, a topic of interest for future studies. In summary, this trial demonstrates that ivosidenib has a favorable safety and tolerability profile, and the preliminary evidence of efficacy observed in patients with MRI-nonenhancing gliomas shows that inhibitors of mutant IDH warrant further investigation for this indication.

Mellinghoff IK, Ellingson BM, Touat M, Maher E, De La Fuente MI, Holdhoff M, et al. Ivosidenib in isocitrate dehydrogenase 1–mutated advanced glioma. J Clin Oncol 2020 Jun 12 [Epub ahead of print].

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