PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.

Broad Institute of MIT and Harvard Cambridge MA 02142 USA; Department of Cancer Biology and Medical Oncology Dana Farber Cancer Institute and Harvard Medical School Boston MA 02115 USA

Broad Institute of MIT and Harvard Cambridge MA 02142 USA; Department of Cancer Biology Dana Farber Boston Children's Cancer and Blood Disorder Center and Harvard Medical School Boston MA 02115 USA

Center for Cancer Research and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria; Research Cluster Translational Cancer Therapy Research University of Vienna and Medical University of Vienna 1090 Vienna Austria

Center for Neuropathology and Prion Research Ludwig Maximilians University Munich Faculty of Medicine Muenchen 80539 Bayern Germany

Central European Institute of Technology Masaryk University 60177 Brno Czech Republic

Central European Institute of Technology Masaryk University 60177 Brno Czech Republic; Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Clinic of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf 20251 Hamburg Germany

Department of Experimental Biology Faculty of Science Masaryk University 61137 Brno Czech Republic; International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Department of Medicine Massachusetts General Hospital Boston MA 02114 USA

Department of Neurology and Neurological Surgery Jefferson University Philadelphia PA 19107 USA

Department of Neurosurgery Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Neurosurgery Massachusetts General Hospital Harvard Medical School Boston MA 02114 USA

Department of Oncology and Children's Research Center University Children's Hospital Zurich 8008 Zurich Switzerland

Department of Pathology Medical University of Vienna 1090 Vienna Austria

Department of Pathology University of Michigan Medical School Ann Arbor MI 48109 USA

Department of Pediatric Hematology Oncology Children's Minnesota Minneapolis MN 55404 USA

Department of Pediatric Oncology Dana Farber Boston Children's Cancer and Blood Disorder Center and Harvard Medical School Boston MA 02215 USA

Department of Pediatric Oncology Dana Farber Boston Children's Cancer and Blood Disorder Center and Harvard Medical School Boston MA 02215 USA; Broad Institute of MIT and Harvard Cambridge MA 02142 USA

Department of Pediatric Oncology Dana Farber Boston Children's Cancer and Blood Disorder Center and Harvard Medical School Boston MA 02215 USA; Department of Pediatrics and Adolescent Medicine Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Pediatric Oncology Dana Farber Boston Children's Cancer and Blood Disorder Center and Harvard Medical School Boston MA 02215 USA; St Anna Children's Hospital Department of Pediatrics and Adolescent Medicine Medical University of Vienna and St Anna Children's Cancer Research Institute 1090 Vienna Austria

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University 662630 Brno Czech Republic

Department of Pediatrics and Adolescent Medicine Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Pediatrics and Adolescent Medicine Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria; Center for Cancer Research and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria; Research Cluster Translational Cancer Therapy Research University of Vienna and Medical University of Vienna 1090 Vienna Austria

Department of Pediatrics and Adolescent Medicine Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria; Department of Neurosurgery Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Pediatrics University of Michigan Medical School Ann Arbor MI 48109 USA

Department of Pediatrics University of Texas Southwestern Medical Center Dallas TX 75390 USA

Department of Radiotherapy Medical University of Vienna 1090 Vienna Austria

Departments of Pediatrics Neurology and Neurological Surgery University of California San Francisco San Francisco CA 94143 USA

Division of Molecular Pathology Institute of Cancer Research SM2 5NG London UK

Division of Neuropathology and Neurochemistry Department of Neurology Medical University of Vienna 1090 Vienna Austria

Division of Neuroradiology and Musculoskeletal Radiology Department of Biomedical Imaging and Image Guided Therapy Medical University of Vienna 1090 Vienna Austria; Research Center of Medical Image Analysis and Artificial Intelligence Danube Private University 3500 Krems an der Donau Austria

Division of Pediatric Hematology and Oncology University Medical Center Göttingen 37099 Göttingen Germany

Great North Childrens Hospital and Newcastle University Newcastle upon Tyne UK; Newcastle Hospitals NHS Foundation Trust NE1 4LP Newcastle UK

Hopp Children's Cancer Center Heidelberg 69120 Heidelberg Germany

Institute for Analytical and General Chemistry Johannes Kepler University 4040 Linz Austria

Lurie Family Imaging Center Center for Biomedical Imaging in Oncology Dana Farber Cancer Institute Boston MA 02210 USA

Sanford Burnham Prebys Medical Discovery Institute San Diego CA 92037 USA

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