10309- ACT-18 A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN DIFFUSE GLIOMA WITH AN IDH1 MUTATION: UPDATED RESULTS

Abstract INTRODUCTION Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in patients with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a Phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics and preliminary objective response rate (ORR) data as of April-29, 2020 were previously reported (Mellinghoff et al. Nat Med 2023). Progression-free survival (PFS) data were not mature at publication time. Herein, we report longer-term follow-up results, including mature PFS. METHODS Patients with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO postsurgery. Secondary objectives included PFS, ORR assessed by investigator in the postsurgery period, and safety profile of VOR and IVO. RESULTS Enrollment completed in April-2019. Of the 49 patients randomized, 46 (24 oligodendroglioma, 20 astrocytoma, one anaplastic oligodendroglioma, one anaplastic oligoastrocytoma) received treatment with either VOR (n=24) or IVO (n=22) after surgery. As of data cutoff (September-23, 2023), 11 (46%) and five (20%) patients remained on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3–NE) for VOR, 38.6 months (18.3–NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas was 46% for VOR and 27% for IVO. Longer safety follow-up will also be presented. CONCLUSIONS These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results in which VOR demonstrated PFS benefit with manageable safety, compared with placebo, in patients with non-enhancing mIDH gliomas.