LBA-02. Molecular Profiling-Guided Individualized Treatment in Children and Young Adults with Newly Diagnosed High-Grade Glioma (Excluding DIPG): A Pilot Trial Demonstrating Promising Outcomes (PNOC008)

Abstract Background PNOC008 was a single-arm, multi-center trial evaluating the feasibility, toxicity, and efficacy of molecularly guided, personalized treatment following upfront radiation for high-grade glioma (HGG), including non-pontine diffuse midline glioma (DMG). Methods Patients aged 21 years with newly diagnosed, localized, hemispheric HGG (Stratum A) or non-pontine DMG (Stratum B) were eligible. Comprehensive molecular profiling was performed (UCSF500 gene panel, WES, WGS, and mRNA-seq). Molecular data were reviewed by a specialized tumor board who recommended up to four FDA-approved drugs. Patients were followed for toxicity and efficacy. Central imaging review was completed. Results Fifty-five patients enrolled between 2018 and 2023 (median age 11 years range 2-20, n = 31 female, n = 29 Stratum A), including H3K27-altered (n = 17), H3/IDH-wildtype diffuse pediatric-type (n = 16), and H3G34-mutant HGG (n = 12). In 44 patients who followed the recommended treatment, median overall survival (OS) from time of study enrollment was 26.5 months in Stratum A (n = 25, lower 95% CI18.5) and 23.5 months in Stratum B (n = 19, lower 95% CI16.8) with median follow-up of 34.5 months (lower 95% CI: 32.2). The median OS was 30 months in H3G34-mutant HGG (n = 10, lower 95% CI: 24.6) and 22.6 months in H3K27-altered DMG (n = 12, lower 95% CI: 19.3). The most common therapies for H3G34-mutant HGG and H3K27-altered DMG were: temozolomide and/or lomustine (18/22, 82%); everolimus (16/22, 73%); dasatinib (8/22, 36%); and olaparib (8/22, 36%). Novel combinations were well tolerated with grade 3 or 4 treatment-related adverse events being mostly hematologic. Fourteen patients (14/43, 33%) received re-irradiation. Clinical and biology correlates include 440 cell-free DNA samples, 350 MR images, 230 quality-of-life questionnaires, and 39 digitized tissue slides. Conclusions A molecularly guided, personalized treatment plan is feasible and well tolerated with encouraging clinical outcomes in children and young adults with HGG and non-pontine DMG. Volumetric tumor analysis and correlative studies are underway.