Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma

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 m IDH1 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 m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

A basic review on systemic treatment options in WHO grade II-III gliomas

“…In IDH-1-mutant glioma, a recently published phase I trial in 66 patients with advanced, IDH-1-mt WHO grade II-IV glioma showed that 85.7% of radiologically non-enhancing and 45.2% of enhancing gliomas achieved stable disease. Furthermore, the median PFS in non-enhancing glioma reached 13.6 months, while that of enhancing glioma was 1.4 months [56]. These results indicate that ivosidenib may be especially active in non-contrast enhancing lower-grade glioma.…”

Ivosidenib, an IDH1 inhibitor, in a patient with recurrent, IDH1 -mutant glioblastoma: a case report from a Phase I study

“…To the best of our knowledge, this is the first case report on an IDH -mutant GBM treated with an IDH inhibitor. The patient was treated as part of a Phase I, multicenter, open-label, dose escalation and expansion study in patients with advanced solid tumors, including glioma (NCT02073994) [ 33 ]. In this study, 66 glioma patients were included and 12 (18.2%) had GBM.…”

“…Preliminary reports indicated that no dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The use of ivosidenib in this study was associated with prolonged tumor control and tumor shrinkage in the patients with advanced glioma [ 33 ]. Pharmacokinetic and pharmacodynamic data from this study have been previously reported [ 29 ].…”

Clinical Management of Diffuse Low-Grade Gliomas

“…By contrast, sunitinib [ 124 ] or imatinib [ 125 , 126 , 127 ] were insufficiently active. Moreover, ivosidenib, an inhibitor of mutant IDH1 , showed interesting results in recurrent LGG with mutated IDH [ 128 ], and a randomized phase 3 study with the similar drug vorasidenib (AG-881) is currently ongoing.…”