DDDR-22. TRANSLATION OF THE PDGFRA/KIT INHIBITOR AVAPRITINIB FOR PEDIATRIC HIGH-GRADE GLIOMA

Abstract Pediatric high-grade glioma (pHGG) is an incurable disease with a median survival of less than 6 months post-progression and no effective targeted therapy. PDGFRA commonly altered in pHGG, but targeting this has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib novel CNS-penetrant PDGFRA/KIT inhibitor that FDA-approved for adults unresectable or metastatic exon 18-mutant gastrointestinal stromal tumor (GIST) being studied CNS tumors. We performed pre-clinical clinical assessment determine the potential suitability avapritinib therapy PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed amplification mutation 10.2% 6.1% respectively. Additionally, expression absence events was significantly increased H3K27-altered diffuse midline (DMG) compared H3-wildtype pHGG. well in: (i) mutant enzyme inhibition wildtype at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), (iv) proliferation/pPDGFRA reduction PDGFRA-amplified pHGG cell lines. treatment aggressive PDX model resulted significant benefit. pursued eight pediatric young adult HGG patients across seven institutions. Patients were mixture local (N = 4) 4); all post-initial radiation, 7/8 having progressed on prior treatment. had amplifications mutations, H3K27M mutations. Therapy generally well-tolerated. 4/8 showed radiographic response avapritinib, one patient demonstrating complete target lesion remains levels patients’ CSF tissue reached micromolar levels. These results demonstrate potent, selective, promising further study relevant alterations.