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Video

Drug discovery, drug resistance

Session: Abstract Concurrent Session: Pediatrics I

DDDR-17 - Clinical response to the PDGFRA/KIT inhibitor avapritinib in pediatric and young adult high-grade glioma patients

Friday, November 17, 2023
4:15 PM – 4:25 PM PT
Location: Room 121-122
Non-CME

    Author(s)

  • Lisa Mayr

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

  • MT

    Maria Trissal

    Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Boston, Massachusetts, United States

  • Kallen Schwark

    University of Michigan
    Ann Arbor, Michigan, United States

    • Oral Abstract Presenter(s)

  • Sina Neyazi

    Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Boston, Michigan, United States

    • Author(s)

  • AB

    Alexander Beck

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
    Munich, Germany

  • JL

    Jenna Labelle

    Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Boston, Massachusetts, United States

  • JM

    Joana Graca Marques

    Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Boston, United States

  • LW

    Liesa Weiler-Wichtl

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

  • SM

    Sibylle Madlener

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

  • SK

    Seongbae Kong

    Department of Pediatrics, University of Michigan Medical School, Ann Arbor
    Ann Arbor, Michigan, United States

  • MM

    Madeline Miclea

    University of Michigan
    Ann Arbor, Michigan, United States

  • JS

    Jeffrey Supko

    Department of Medicine, Massachusetts General Hospital
    Boston, Massachusetts, United States

  • AG

    Armin Sebastian Guntner

    Institute of Analytical Chemistry, Johannes Kepler University
    Linz, Austria

  • HP

    Hana Palova

    Central European Institute of Technology, Masaryk University
    Brno, Czech Republic

  • JN

    Jakub Neradil

    Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University
    Brno, Czech Republic

  • Natalia Stepien

    Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center
    Vienna, Austria

  • Daniela Loetsch-Gojo

    Department of Neurosurgery, Medical University of Vienna, Vienna, Austria
    Vienna, Austria

  • CD

    Christian Dorfer

    Department of Neurosurgery, Medical University of Vienna
    Vienna, Austria

  • KD

    Karen Dieckmann

    Department of Radiotherapy, Medical University of Vienna
    Vienna, Austria

  • AP

    Andreas Peyrl

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

  • AA

    Amedeo A A. Azizi

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

  • AB

    Alicia-Christina Baumgartner

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

  • OS

    Ondrej Slaby

    Central European Institute of Technology, Masaryk University, Brno
    Brno, Czech Republic

  • PP

    Petra Pokorna

    Central European Institute of Technology, Masaryk University
    Brno, Czech Republic

  • FD

    Frank Dubois

    Dana-Farber Cancer Institute
    Boston, Massachusetts, United States

  • NG

    Noah Greenwald

    Stanford University
    Stanford, California, United States

  • PB

    Pratiti Bandopadhayay

    Dana-Farber Cancer Institute
    Boston, Massachusetts, United States

  • RB

    Rameen Beroukhim

    Center for Neuro-Oncology, Dana-Farber Cancer Institute
    Boston, Massachusetts, United States

  • Keith L. Ligon

    Brigham and Women's Hospital
    Boston, Massachusetts, United States

  • CK

    Christof Kramm

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

  • AB

    Annika Bronsema

    Clinic of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf
    Hamburg, Germany

  • SB

    Simon Bailey

    Great North Childrens Hospital and Newcastle University
    Newcastle upon Tyne, United Kingdom

  • AG

    Ana Guerreiro Stuecklin

    Kispi
    Zurich, Switzerland

  • Sabine Mueller

    University of California, San Francisco
    San Francisco, California, United States

  • MS

    Mary Skrypek

    Department of Pediatric Hematology-Oncology, Children’s Minnesota
    Minneapolis, United States

  • NM

    Nina Martinez

    Department of Neurology & Neurological Surgery, Jefferson University
    Philadelphia, Pennsylvania, United States

  • Daniel C C. Bowers

    Department of Pediatrics, University of Texas Southwestern Medical Center
    Dallas, Texas, United States

  • DJ

    David TW Jones

    German Cancer Research Center (DKFZ)
    Heidelberg, Germany

  • CJ

    Chris Jones

    Division of Molecular Pathology, Institute of Cancer Research
    London, United Kingdom

  • NJ

    Natalie Jaeger

    Hopp Children's Cancer Center Heidelberg (KiTZ) & Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ)
    Heidelberg, Germany

  • JS

    Jaroslav Sterba

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

  • LM

    Leonhard Müllauer

    Department of Pathology, Medical University of Vienna
    Vienna, Austria

  • CH

    Christine Haberler

    Medical University of Vienna
    Vienna, Austria

  • CK

    Chandan Kumar-Sinha

    University of Michigan
    Ann Arbor, Michigan, United States

  • AC

    Arul Chinnaiyan

    University of Michigan
    Ann Arbor, Michigan, United States

  • RM

    Rajen Mody

    University of Michigan
    Ann Arbor, Michigan, United States

  • JF

    Julia Furtner-Srajer

    Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna
    Vienna, Austria

  • Carl J. Koschmann

    University of Michigan
    Ann Arbor, Michigan, United States

  • JG

    Johannes Gojo

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

  • Mariella G. Filbin

    Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Boston, Massachusetts, United States

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.