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Abstract
PDGFRA has been shown to be commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. Here, we performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations (mutations and/or amplifications) in ~14.9% of patients. We tested a panel of patient-derived HGG and H3K27M DMG models against a range of PDGFRA inhibitors, and found that avapritinib outperformed other inhibitors in terms of (1) in vitro efficacy, (2) selectivity for PDGFRA inhibition and (3) blood brain barrier penetration, and demonstrated significant survival impact and PDGFRA pathway inhibition in two orthotopic H3K27M DMG mouse models. We furthermore report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib was generally well tolerated with a manageable safety profile and no significant safety concerns. Preliminary data reveal radiographic response evaluated by RAPNO criteria in 3/7 (42%) patients with evaluable lesions. Complete or partial response was observed in 2 of 8 patients (25%); one patient showed stable disease; 5 of 8 patients progressed on therapy (62%). Molecular profiling of treated patients revealed PDGFRA amplification in 4 of 8 patients, PDGFRA receptor mutations in 4 of 8 patients. One patient with PDGFRA/KIT amplification developed a spontaneous EGFR gain and a secondary PDGFRA mutation in a cerebellar metastatic lesion that progressed on avapritinib therapy. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in HGG patients.