A pilot trial of perioperative IDH Inhibition in treatment-naïve IDH-mutant glioma
Mutant-IDH (mIDH) inhibition significantly improves progression free survival in patients with mIDH WHO grade 2 glioma, however almost all patients will progress, and there is a lack of understanding on the mechanisms of adaptation to mIDH inhibition. In the first pre- and post-treatment perioperative trial in patients with mIDH1 low-grade glioma, we tested safusidenib (AB-218 / DS-1001b), an oral, blood brain barrier penetrant IDH1 R132X inhibitor, in a single arm, open label study. The primary endpoint demonstrated the feasibility and acceptability of conducting a two-stage perioperative trial and treatment was well tolerated, with ongoing follow-up for safety and efficacy. Tumor 2-hydroxyglutarate quantification revealed on-target activity, resulting in significant alterations in differentiation programs and neural excitability, functionally validated by patch clamp electrophysiology. Taken together, these results provide a detailed understanding on mechanisms of mIDH inhibition in glioma and the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, advancing drug development in glioma. Funded by AnHeart Therapeutics (a Nuvation Company) and the Victorian Government; ClinicalTrials.gov number NCT05577416. Overall design: Single nuclei gene expression was profiled using the Chromium Single Cell Gene Expression Flex (10x Genomics) from tumor resections of patients with IDH-mutated low grade glioma (n = 8 astrocytoma, n = 3 oligodendroglioma).