DDDR-22 - Translation of the PDGFRA/KIT inhibitor avapritinib for pediatric high-grade glioma

Saturday, November 19, 2022

4:55 PM – 5:05 PM ET

Location: Ballroom A

Oral Abstract Presenter(s)

Kallen Schwark

University of Michigan
Ann Arbor, United States

Author(s)

Lisa Mayr, MD

Medical University of Vienna
Vienna, Austria
MT

Maria Trissal

Dana-Farber Cancer Institute
Boston, United States
JL

Jenna Labelle

Dana-Farber Cancer Institute
Boston, United States
SK

Seongbae Kong

University of Michigan
Ann Arbor, United States
AG

Andrew Groves

Dana-Farber Cancer Institute
Boston, United States
JS

Jeffrey Supko

Massachusetts General Hospital
Boston, United States
OH

Olivia A. Hack, B.Sc.

Dana-Farber Boston Children's Cancer and Blood Disorders Center
Boston, United States
JM

Joana Marques

Dana-Farber Cancer Institute
Boston, United States
Eshini Panditharatna

Dana-Farber Boston Children's Cancer and Blood Disorders Center
Boston, United States
FD

Frank Dubois, Massachusetts, PhD

Dana-Farber Cancer Institute
Boston, United States
NG

Noah Greenwald

Dana-Farber Cancer Institute
Boston, United States
PB

Pratiti Bandopadhayay, MBBS PhD

Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston MA
Boston, United States
Keith L. Ligon, MD, PhD

Dana-Farber Cancer Institute
Boston, United States
JF

Julia Furtner-Srajer

Medical University of Vienna
Vienna, Austria
LW

Liesa Weiler-Wichtl

Medical University of Vienna
Vienna, Austria
UL

Ulrike Leiss

Medical University of Vienna
Vienna, Austria
VR

Verena Rosenmayr, Mag.

Medical University of Vienna
Vienna, Austria
SM

Sibylle Madlener, PhD

Medical University of Vienna
Vienna, Austria
Natalia Stepien, MD

Medical University of Vienna
Vienna, Austria
DL

Daniela Lötsch-Gojo

Medical University of Vienna
Vienna, Austria
CD

Christian Dorfer, MD

Medical University of Vienna/ University Hospital Vienna, Austria
Vienna, Austria
KD

Karin Dieckmann

Medical University of Vienna
Vienna, Austria
AA

Amedeo A. Azizi, MD

Medical University of Vienna / University Hospital Vienna, Austria
Vienna, Austria
AG

Armin Guntner

Johannes Kepler University Linz
Linz, Austria
HP

Hana Palova

Masaryk University
Brno, Czech Republic
OS

Ondrej Slaby, n/a

Central European Institute of Technology (CEITEC), Masaryk University
Brno, Czech Republic
PP

Petra Pokorná

CEITEC
Brno, Czech Republic
RB

Rameen Beroukhim, MD, PhD

Dana-Farber Cancer Institute
Boston, United States
CK

Christof Kramm

Georg August University Gottingen
Gottingen, Germany
DJ

David T. W. Jones, PhD

Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ)
Heidelberg, Germany
J�

Jaroslav Štěrba

Masaryk University
Brno, Czech Republic
LM

Leonhard Mullauer

Medical University of Vienna
Vienna, Austria
CH

Christine Haberler, MD

Medical University of Vienna
Vienna, Austria
NP

Nisha Perez

Blueprint Medicines
Cambridge, United States
SK

Sean Kim, PhD

Blueprint Medicines
Cambridge, United States
AH

Anthony Hsieh, MD

Blueprint Medicines
Cambridge, United States
SD

Sasa Dimitrijevic, PhD

Blueprint Medicines (Switzerland) GmbH
Zug, Switzerland
MS

Mary Skrypek

Children's Minnesota
Minneapolis, United States
NM

Nina Martinez, MD

Jefferson University
Philadelphia, United States
Daniel C. Bowers, MD

UT Southwestern
Dallas, United States
Mariella G. Filbin, MD PhD (she/her/hers)

Dana-Farber Boston Children’s Cancer and Blood Disorders Center
Boston, United States
JG

Johannes Gojo, MD

Medical University of Vienna
Vienna, Austria
Carl J. Koschmann, MD

Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA
Ann Arbor, United States

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 is commonly altered in pHGG, but targeting PDGFRA in this disease has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib is a novel and CNS-penetrant PDGFRA/KIT inhibitor that is FDA-approved for adults with unresectable or metastatic PDGFRA exon 18-mutant gastrointestinal stromal tumor (GIST) and is being studied in CNS tumors.
We performed a pre-clinical and clinical assessment to determine the potential suitability of avapritinib therapy in PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed PDGFRA amplification and mutation in 10.2% and 6.1% of pHGG, respectively. Additionally, PDGFRA expression in the absence of genetic events was significantly increased in H3K27-altered diffuse midline glioma (DMG) compared to H3-wildtype pHGG. Avapritinib performed well in: (i) mutant PDGFRA enzyme inhibition and wildtype inhibition at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), and (iv) proliferation/pPDGFRA reduction in PDGFRA-amplified and mutant pHGG cell lines. Avapritinib treatment in an aggressive PDX model of pHGG resulted in significant survival benefit.
We pursued treatment of eight pediatric and young adult HGG patients with avapritinib across seven institutions. Patients were a mixture of local (N = 4) and metastatic disease (N = 4); all patients were post-initial radiation, with 7/8 having progressed on prior treatment. 7/8 patients had PDGFRA amplifications or mutations, and 7/8 had H3K27M mutations. Therapy was generally well-tolerated. 4/8 patients showed radiographic response to avapritinib, with one patient demonstrating complete response of target lesion and remains on therapy. Avapritinib levels in patients’ CSF and brain tumor tissue reached micromolar levels. These results demonstrate that avapritinib is a potent, selective, and CNS-penetrant PDGFRA/KIT inhibitor that is promising for further study in pHGG with relevant alterations.