Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition
Liana Nobre, Michal Zápotocký, Vijay Ramaswamy, Scott Ryall, Julie Bennett, Daniel Alderete, Julia Balaguer Guill, Lorena Baroni, Ute Bartels, Abhishek Bavle, Miriam Bornhorst, Daniel R. Boué, Adela Cañete, Murali Chintagumpala, Scott Coven, Ofelia Cruz, Sonika Dahiya, Peter B. Dirks, Ira J. Dunkel, David D. Eisenstat, Cécile Faure‐Conter, Elizabeth Finch, Jonathan L. Finlay, Didier Frappaz, Maria Luisa Garrè, Karen Gauvain, Anne Grete Bechensteen, Jordan R. Hansford, Inga Harting, Péter Hauser, Lili‐Naz Hazrati, Annie Huang, Sarah G. Injac, Valentina Iurilli, Matthias A. Karajannis, Gurcharanjeet Kaur, Martin Kynčl, Lenka Krsková, Normand Laperrière, Valérie Larouche, Álvaro Lassaletta, Sarah Leary, Frank Y. Lin, Samantha Mascelli, Tara McKeown, Till Milde, Andrés Morales La Madrid, Giovanni Morana, Helena Mörse, Naureen Mushtaq, Diana S. Osorio, Roger J. Packer, Zdeněk Pavelka, Eduardo Quiroga-Cantero, James T. Rutka, Magnus Sabel, Duarte Salgado, Palma Solano‐Páez, Jaroslav Štěrba, Jack Su, David Sumerauer, Michael D. Taylor, Helen Toledano, Derek S. Tsang, Mariana Valente Fernandes, Frank K.H. van Landeghem, Cornelis M. van Tilburg, Bev Wilson, Olaf Witt, Josef Zámečnı́k, Éric Bouffet, Cynthia Hawkins, Uri Tabori
Abstract
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.