Abstract
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.
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