Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition

Liana Nobre, Michal Zapotocky, Vijay Ramaswamy, Scott Ryall, Julie Bennett, Daniel Alderete, Julia Balaguer Guill, Lorena Baroni, Ute Bartels, Abhishek Bavle, Miriam Bornhorst, Daniel R. Boue, Adela Canete, Murali Chintagumpala, Scott L. Coven, Ofelia Cruz, Sonika Dahiya, Peter Dirks, Ira J. Dunkel, David EisenstatCecile Faure Conter, Elizabeth Finch, Jonathan L. Finlay, Didier Frappaz, Maria Luisa Garre, Karen Gauvain, Anne Grete Bechensteen, Jordan R. Hansford, Inga Harting, Peter Hauser, Lili Naz Hazrati, Annie Huang, Sarah G. Injac, Valentina Iurilli, Matthias Karajannis, Gurcharanjeet Kaur, Martin Kyncl, Lenka Krskova, Normand Laperriere, Valerie Larouche, Alvaro Lassaletta, Sarah Leary, Frank Lin, Samantha Mascelli, Tara McKeown, Till Milde, Andres Morales la Madrid, Giovanni Morana, Helena Morse, Naureen Mushtaq, Diana S. Osorio, Roger Packer, Zdenek Pavelka, Eduardo Quiroga-Cantero, James Rutka, Magnus Sabel, Duarte Salgado, Palma Solano, Jaroslav Sterba, Jack Su, David Sumerauer, Michael D. Taylor, Helen Toledano, Derek S. Tsang, Mariana Valente Fernandes, Frank van Landeghem, Cornelis M. van Tilburg, Bev Wilson, Olaf Witt, Josef Zamecnik, Eric Bouffet, Cynthia Hawkins, Uri Tabori

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57 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)561-571
Number of pages11
JournalJCO Precision Oncology
Publication statusPublished - 2019


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