INNV-39. Response to next interventions after treatment with off-label ivosidenib in patients with mutant IDH low grade glioma

Abstract The introduction of mutant IDH inhibitors (mIDHi) has transformed the treatment landscape for patients with low-grade gliomas (LGG). However, optimal strategies for tumor control following progression on mIDHi therapy remain uncertain. We describe outcomes of next-line interventions in a real-world cohort of patients with mutant IDH (mIDH) LGG who progressed on ivosidenib. Out of a cohort of 74 patients with mIDH LGG treated with ivosidenib monotherapy at a single center, eight were identified who experienced radiographic progression per RANO criteria and subsequently received next-line therapy between October 2020 and June 2025. Clinical characteristics and imaging findings, including volumetric tumor assessments, were analyzed. In this cohort (n=8), patients were 24–58 years old at ivosidenib initiation. Diagnoses included WHO grade 2 astrocytoma (n=4) and oligodendroglioma (n=4). Prior therapies included maximal safe resection (n=7), temozolomide (n=5), and lomustine (n=1); none had received prior radiation therapy (RT). Time to progression on ivosidenib ranged from 2 to 42 months. Next interventions included lomustine monotherapy (n=2), RT with concurrent temozolomide (n=4), RT alone (n=1), and re-resection followed by chemoradiation (n=1). Following next line therapy, five patients demonstrated radiographic improvement, two had stable disease, and one had changes attributed to post-treatment effect. Volumetric studies within 6 months before and after progression on ivosidenib showed an average tumor growth of +5.2±3.2% per month prior to progression and shrinkage of -13.1±3.9% per month following next-line intervention. Median follow-up after progression was 15±11 months. At last follow-up, six patients had tumor control without clinical or radiographic worsening. Two patients experienced disease progression, both of whom had high-risk features, including absence of prior resection, tumor transformation to higher grade, neurologic exam decline, and poor chemotherapy tolerance. In this early real-world cohort, most patients with mIDH LGG achieved clinical and radiographic stability after progression on ivosidenib using next-line chemotherapy and RT. These findings support the feasibility of cytotoxic strategies following mIDH inhibition.