DDDR-17. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS

• DOI: 10.1093/neuonc/noad179.0411
• Publication Date: 2023-11-11T23:09:39Z
• Authors: Lisa Mayr; Maria Trissal; Kallen Schwark; Sina Neyazi; Alexander Beck; Jenna Labelle; Joana Graca Marques; Liesa Weiler-Wichtl; Sibylle Madlener; Seongbae Kong; Madeline Miclea; Jeffrey Supko; Armin Sebastian G...; Hana Palova; Jakub Neradil; Natalia Stepien; Daniela Loetsch-Gojo; Christian Dorfer; Karen Dieckmann; Andreas Peyrl; Amedeo A Azizi; Alicia-Christina ...; Ondrej Slaby; Petra Pokorna; Frank Dubois; Noah Greenwald; Pratiti Bandopadh...; Rameen Beroukhim; Keith Ligon; Christof Kramm; Annika Bronsema; Simon Bailey; Ana Guerreiro Stu...; Sabine Mueller; Mary Skrypek; Nina Martinez; Daniel C Bowers; David Jones; Chris Jones; Natalie Jaeger; Jaroslav Sterba; Leonhard Müllauer; Christine Haberler; Chandan Kumar-Sinha; Arul Chinnaiyan; Rajen Mody; Julia Furtner-Srajer; Carl Koschmann; Johannes Gojo; Mariella Filbin
• Keywords: PDGFRA

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