Abstract
Abstract Isocitrate dehydrogenase 1 mutations (mIDH1) occur in ~80% of grade 2/3 gliomas. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mIDH1/2 enzymes, is an investigational treatment for mIDH gliomas. A neoadjuvant perioperative study in grade 2/3 mIDH gliomas suggested VOR renders the tumor immune microenvironment amenable to immune checkpoint blockade. This study (NCT05484622) evaluates safety/tolerability of VOR plus pembrolizumab to determine the recommended combination dose (RCD) (safety lead-in phase), and CD3+ T-cell infiltration in tumors following preoperative treatment (perioperative phase). Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an IDH1-R132H mutation were dosed in the safety lead-in phase: median age 39 (range, 34–60) years, 3 (43%) female, 6 (86%) grade 3 at screening. Patients received VOR 40 mg orally once daily (QD) plus pembrolizumab 200 mg intravenously once every 3 weeks (Q3W). As of April 29, 2023, patients received a median of 2 (range, 2–5) cycles with six (86%) ongoing; one (14%) discontinued due to disease progression. No dose-limiting toxicities (DLTs), adverse events (AEs) leading to study drug discontinuation, or AEs of special interest (AESI, elevated liver transaminases) were reported during the DLT evaluation period. Six (86%) patients experienced a treatment-related AE, none of which were grade ≥ 3. One (14%) patient experienced a serious, related AE of dysphasia (leading to VOR and pembrolizumab interruption) that subsequently resolved; both drugs were resumed. After the data cut-off, one patient (14%) experienced a grade 2 AESI. Based on safety review committee evaluation, VOR 40 mg QD + pembrolizumab 200 mg Q3W was confirmed as the RCD for the recently initiated perioperative phase. In this phase, ~60 patients will be randomized 1:1:1 to the RCD, VOR 40 mg QD alone, or no treatment prior to surgery. All patients can receive the RCD post-surgery. Funding: Servier and Merck & Co., Inc.