PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Aga Khan University Hospital Karachi Pakistan

Arthur and Sonia Labatt Brain Tumour Research Centre Hospital for Sick Children Toronto ON Canada

Children's National Health System Washington DC

Department of Hematology and Oncology Hospital for Sick Children Toronto ON Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada

Department of Medical Biophysics University of Toronto Toronto ON Canada

Department of Pediatric Laboratory Medicine Hospital for Sick Children Toronto ON Canada

Department of Surgery University of Ontario Toronto ON Canada

Developmental and Stem Cell Biology Program Hospital for Sick Children Toronto ON Canada

Division of Neurosurgery Hospital for Sick Children Toronto ON Canada

Division of Pediatric Hematology and Oncology Department of Pediatrics Indiana University Indianapolis IN

G Gaslini Children's Hospital Genoa Italy

Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Hospital Infantil Universitario Niño Jesús Madrid Spain

Hospital Infantil Virgen del Rocío Sevilla Spain

Hospital of Pediatrics SAMIC Prof Dr Juan P Garrahan Buenos Aires Argentina

Hospital Sant Joan de Déu Barcelona Spain

Hospital Universitario y Politecnico La Fe University of Valencia Valencia Spain

Institute d'Hémato Oncologie Pédiatrique Centre Leon Berard Lyon France

Jimmy Everest Section of Pediatric Heamatology Oncology University of Oklahoma Health Sciences Center Oklahoma City OK

Lund University Lund Sweden

Memorial Sloan Kettering Cancer Center New York NY

Nationwide Children's Hospital and Ohio State University Columbus OH

Oslo University Hospital Oslo Norway

Portuguese Oncology Institute Lisbon Portugal

Royal Children's Hospital Murdoch Children's Research Institute University of Melbourne Melbourne VIC Australia

Sahlgrenska University Hospital University of Gothenburg Gothenburg Sweden

Schneiders Children's Medical Center of Israel Petah Tikva Israel

Seattle Children's Hospital Seattle WA

Semmelweis University Budapest Hungary

Stollery Children's Hospital University of Alberta Edmonton AB Canada

Texas Children's Cancer Center Houston TX

Universite Laval Quebec City QC Canada

University Hospital Brno Masaryk University and ICRC Brno Brno Czech Republic

University of North Carolina at Chapel Hill Chapel Hill NC

Washington University School of Medicine St Louis MO

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Novel BRAF gene fusions and activating point mutations in spindle cell sarcomas with histologic overlap with infantile fibrosarcoma