Response to Next Intervention After Off-label Ivosidenib Treatment Failure in Patients With Mutant IDH Low Grade Glioma
Maria Minor1, Jikai Zhang2, Rana Elkholi3, Jonathan Dewey3, Mallika Patel1, Alicia Savelli1, Margaret Johnson1, Kristen Batich1, Justin Low4, Madison Shoaf1, Mustafa Khasraw5, Annick DesJardins1, Henry Friedman1, David Ashley1, Evan Calabrese1, Katherine Peters1
1Duke University Medical Center, 2Duke University, 3Servier, 4Duke University School of Medicine, 5The Preston Robert Tisch Brain Tumor Center
Objective:

To characterize the outcomes of patients with low grade gliomas who undergo next-line therapies following disease progression after IDH inhibition

Background:

IDH inhibitors (IDHi) have reshaped the treatment landscape for low-grade glioma (LGG), yet optimal strategies following IDHi treatment failure remain unclear. We report the outcomes of next-line therapies in patients with IDH1-mutant LGG who progressed on ivosidenib.

Design/Methods:

Among 74 patients treated with ivosidenib monotherapy at our center, eight experienced progression per RANO criteria and subsequently received next-line therapy between October 2020 and October 2025. Clinical and imaging data, including volumetric tumor assessments, were analyzed. 

Results:

Patients (n=8) were 34–58 years old at the time of next intervention. Diagnoses included grade 2 astrocytoma (n=3) and oligodendroglioma (n=5). In addition to ivosidenib, prior treatments included maximal safe resection (n=7), temozolomide (n=4), and lomustine (n=1). Median time to progression on ivosidenib was 16 months (range 2–42). Next-line therapies included radiation therapy (RT) with concurrent temozolomide (n=4), re-resection plus chemoradiation (n=1), RT alone (n=1), and lomustine monotherapy (n=2). Post-treatment imaging showed radiographic improvement in five patients, stable disease in two, and treatment-related changes in one. Volumetric analysis revealed a median 42% tumor reduction 3–6 months following next interventions. Median tumor-specific growth rates decreased from +5.0% to –8.2% per month pre- vs post-intervention. At last follow-up (range 18.3-110.9 months), six patients maintained tumor control with clinical and radiographic stability. Two patients had disease progression, both of whom had high-risk features including no prior resection, tumor transformation, and poor chemotherapy tolerance.

Conclusions:
In this real-world cohort, most patients with IDH1-mutant LGG achieved radiographic and clinical stability following progression on ivosidenib with using next-line chemotherapy and RT. These findings support the feasibility of cytotoxic strategies following IDHi treatment failure.
10.1212/WNL.0000000000216670
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.