Ivosidenib for the treatment of IDH1-mutant glioma, grades 2-4: Tolerability, predictors of response, and outcomes

Abstract

Background: Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel targeted approach for treating IDHm glioma patients, yet their optimal use in clinical practice outside of clinical trials remains undefined. This study describes the real-world utilization of the mutant IDH1 inhibitor (IDHi), ivosidenib, in patients with IDHm glioma.

Methods: We retrospectively reviewed clinical and radiographic data from patients with IDHm glioma treated with ivosidenib monotherapy from 2020 to 2024 at the Dana-Farber Cancer Institute and Massachusetts General Hospital.

Results: This cohort included 74 patients with a median age of 39. There were 35 astrocytomas and 39 oligodendrogliomas, with 49, 23, and 2, grade 2, 3, and 4 tumors, respectively. Nineteen patients (26%) experienced an adverse event, although only 1 patient discontinued ivosidenib for adverse events. Median progression-free survival was 31 months and median overall survival was not reached. Seven patients (9%) had partial response, 3 (4%) had minor response, 47 (64%) had stable disease, and 17 (23%) had progressive disease. The presence of enhancing disease at ivosidenib initiation was associated with lower disease control rates (DCR) whereas DCR differences were not detected based on grade (grade 2 vs. 3), tumor histology, or age. Subsequent-line ivosidenib use had lower DCR although this may have been explained by enrichment of patients with enhancing disease.

Conclusions: In this large cohort of IDHm glioma patients, ivosidenib was well tolerated. Our results support the use of IDHi therapy in patients with grade 2 or 3 astrocytoma or oligodendroglioma and highlight limited effectiveness in patients with enhancing disease.

Keywords: IDH inhibitor; IDH-mutant glioma; astrocytoma; ivosidenib; oligodendroglioma.

Figure 1.

Patient cohort and treatment. Each horizontal bar of the swimmer plot represents length of time (in months) an individual patient was taking ivosidenib. All patients are represented on this plot. Patients are divided into those who took ivosidenib as first-line treatment (prior to any chemotherapy and/or XRT) in the top half and those who started ivosidenib as subsequent-line treatment (after having done chemotherapy and/or XRT). An arrow at the end of the bar signifies that the patient had not discontinued ivosidenib by the time of analysis. Each patient’s BOR (per RANO 2.0 criteria) is indicated by a symbol and is graphed on the x-axis when it took place. Patients are color-coded according to WHO grade. Just to the left of each bar designates a patient’s histology (O vs A) and enhancement pattern (NE, E, E*, and E**). A = astrocytoma; BOR = best overall response; E = enhancing disease when ivosidenib was started; E* = nonenhancing disease when ivosidenib was started but later developed enhancement; E** = initially had enhancing disease but enhancing areas were entirely resected by the time ivosidenib was started; MR = minor response; NE = nonenhancing disease only; O = oligodendroglioma; PD = progressive disease; PR = partial response; SD = stable disease; XRT = radiation therapy.

Figure 2.

Radiographic response. Each vertical bar of the waterfall plot represents the percent change from baseline to best response in tumor cross-product (either nonenhancing disease in A, C, and D, or enhancing disease in B) for each patient. Each bar is color-coded according to their best overall response (taking both enhancing and enhancing disease into account per RANO 2.0 criteria). (A) Bars represent nonenhancing disease in all patients, (B) bars represent enhancing disease in the subset of patients who had enhancing disease when ivosidenib was started (only 1 patient with enhancing disease at ivosidenib onset was treated with first-line therapy so enhancing disease was not segmented here by line therapy), (C) bars represent nonenhancing disease in the subset of patients who started ivosidenib as first-line treatment, (D) bars represent nonenhancing disease in the subset of patients without enhancing disease who started ivosidenib as subsequent-line treatment. BOR = best overall response; MR = minor response; PD = progressive disease; PR = partial response, SD = stable disease.

Figure 3.

Survival analysis. Kaplan–Meier curves illustrate overall survival (A and C) and progression-free survival (B and D) in patients who started ivosidenib as first line versus subsequent line (A and B) and in patients with nonenhancing versus enhancing disease when ivosidenib was started (C and D). Each plot encompasses all patients from this study. P-values provided are for log-rank tests.

Figure 4.

Disease control rate (DCR). Bar graphs demonstrating the proportion of patients with DCR (defined by partial response + minor response + stable disease) within each cohort: patients with enhancing disease versus no enhancing disease when ivosidenib was started; patients who started ivosidenib as first-line versus subsequent-line treatment; WHO grade 2 versus 3; astrocytoma vs oligodendroglioma. The total sample size of each group is shown numerically within each bar. Comparing groups with chi-square test, there was a statistically significant (P < .05) difference between nonenhancing versus enhancing and first-line versus subsequent-line ivosidenib but there was no statistically significant difference based on grade and tumor type. Astro = astrocytoma; DCR = disease control rate; oligo = oligodendroglioma.