Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

Eric Bouffet; Jordan R Hansford; Maria Luisa Garrè; Junichi Hara; Ashley Plant-Fox; Isabelle Aerts; Franco Locatelli; Jasper van der Lugt; Ludmila Papusha; Felix Sahm; Uri Tabori; Kenneth J Cohen; Roger J Packer; Olaf Witt; Larissa Sandalic; Ana Bento Pereira da Silva; Mark Russo; Darren R Hargrave

doi:10.1056/NEJMoa2303815

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

N Engl J Med. 2023 Sep 21;389(12):1108-1120. doi: 10.1056/NEJMoa2303815.

Authors

Eric Bouffet¹, Jordan R Hansford¹, Maria Luisa Garrè¹, Junichi Hara¹, Ashley Plant-Fox¹, Isabelle Aerts¹, Franco Locatelli¹, Jasper van der Lugt¹, Ludmila Papusha¹, Felix Sahm¹, Uri Tabori¹, Kenneth J Cohen¹, Roger J Packer¹, Olaf Witt¹, Larissa Sandalic¹, Ana Bento Pereira da Silva¹, Mark Russo¹, Darren R Hargrave¹

Affiliation

¹ From the Hospital for Sick Children, University of Toronto, Toronto (E.B., U.T.); the Royal Children's Hospital, University of Melbourne, Murdoch Children's Research Institute, Melbourne, VIC, and the Women's and Children's Hospital, South Australia Health and Medical Research Institute, South Australian immunoGENomics Cancer Institute, and the University of Adelaide, Adelaide - all in Australia (J.R.H.); IRCCS Giannina Gaslini Institute, Genoa (M.L.G.), and IRCCS Bambino Gesù Children's Hospital, Catholic University of the Sacred Heart, Rome (F.L.) - both in Italy; Osaka City General Hospital, Osaka, Japan (J.H.); the Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago (A.P.-F.); Institut Curie, SIREDO Oncology Center, Paris Sciences et Lettres Research University, Paris (I.A.); the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (J.L.); Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow (L.P.); the Department of Neuropathology and Clinical Cooperation Unit Neuropathology (F.S.) and the Hopp Children's Cancer Center, German Consortium for Translational Cancer Research, and National Center for Tumor Diseases, German Cancer Research Center, Heidelberg University Hospital, Heidelberg, Germany (F.S., O.W.); the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (K.J.C.); Children's National Hospital, Washington, D.C. (R.J.P.); Novartis Pharma, Basel, Switzerland (L.S., A.B.P.S.); Novartis Pharmaceuticals, East Hanover, NJ (M.R.); and the University College London Great Ormond Street Institute of Child Health, London (D.R.H.).

PMID: 37733309
DOI: 10.1056/NEJMoa2303815

Abstract

Background: Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy.

Methods: In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival.

Results: A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy.

Conclusions: Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy. (Funded by Novartis; ClinicalTrials.gov number, NCT02684058.).

Publication types

Randomized Controlled Trial
Clinical Trial, Phase II

MeSH terms

Antineoplastic Agents* / therapeutic use
Child
Glioma* / drug therapy
Glioma* / genetics
Humans
Mutation
Proto-Oncogene Proteins B-raf* / genetics

Substances

BRAF protein, human
dabrafenib
Proto-Oncogene Proteins B-raf
trametinib
Antineoplastic Agents

Associated data

ClinicalTrials.gov/NCT02684058