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CNS tumours

3798 - The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas


07 Oct 2016


CNS tumours


Mark Kieran


Annals of Oncology (2016) 27 (6): 1-36. 10.1093/annonc/mdw435


M.W. Kieran1, E. Bouffet2, U. Tabori3, A. Broniscer4, K. Cohen5, J. Hansford6, B. Geoerger7, P. Hingorani8, I. Dunkel9, M. Russo10, L. Tseng10, Q. Liu10, N. Nebot10, J. Whitlock2, D. Hargrave11

Author affiliations

  • 1 Pediatric Medical Neuro-oncology, Harvard Medical School, Boston Children’s Hospital, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 2 Haematology/oncology, University of Toronto, The Hospital for Sick Children, Toronto/CA
  • 3 Division Of Haematology/oncology, Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto/CA
  • 4 Oncology Department, St. Jude Children’s Research Hospital, Memphis/US
  • 5 Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore/US
  • 6 Children's Cancer Centre, The Royal Children’s Hospital, University of Melbourne, Murdoch Children’s Research Institute, Melbourne/AU
  • 7 Department Of Pediatric And Adolescent Oncology, Gustave Roussy, 94805 - Villejuif/FR
  • 8 Hematology/oncology, Phoenix Children’s Hospital, Phoenix/US
  • 9 Pediatric Oncology, Memorial Sloan Kettering Cancer Center, New York/US
  • 10 Global Oncology, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 11 Haematology And Oncology, Great Ormond Street Hospital, WC1N 3JH - London/GB


Abstract 3798


BRAF V600 mutations are present in 15%-20% patients (pts) with pediatric low-grade gliomas (pLGG). Relative to pts with BRAF V600–wild type pLGG, pts with BRAF V600E–mutant pLGG had poor survival and lower objective response rates (ORR) to initial (29%) and 2nd-line (11%) chemotherapy (Lassaletta A, ASCO 2016). There remains a need for improved treatment options for this pLGG subgroup. Dabrafenib is a potent and selective inhibitor of the V600–mutant form of the BRAF kinase. We report the results of the first study of dabrafenib in pediatric pts with BRAF V600–mutant recurrent or progressive LGG.


Thirty-two pts aged 2-17 y with BRAF V600–mutant relapsed or refractory LGG were enrolled Dec 2013 to Jul 2015 across 4 dose levels of dabrafenib monotherapy up to and including the recommended phase 2 dose (RP2D; 4.5 mg/kg/day in pts ≥ 12 y, 5.25 mg/kg/day in pts < 12 y, divided into 2 equal doses per day [Kieran MW, ASCO 2015]). The results presented are from all 32 pts with pLGG (15 pts enrolled into the dose-finding and 17 pts treated after determination of the RP2D). Overall, 24 pts were treated at the RP2D.


Twenty-two of the 32 pts remained on study as of April 2016. Adverse events were generally similar to those observed in adults, with frequent low-grade pyrexia, vomiting, fatigue, headache and rash. There have been no reports of cutaneous squamous cell carcinoma. The most frequent grade 3 or 4 AE was pneumonia, in 3 pts. 1 pt experienced a significant allergic reaction on day 2 of dosing and again upon rechallenge and was discontinued from study. Independent confirmed overall response by RANO criteria was 2 CRs and 11 PRs in this 2nd-line setting (N = 32, ORR 41% [95% CI, 24%-59%]), with a median duration of response of 11 months (8 responders ongoing). There were an additional 13 pts (41%) with SD of 6 months or greater duration (11 ongoing). Investigator confirmed overall response was 1 CR and 22 PRs (ORR 72% [95% CI, 53%-86%]).


Targeted therapy using dabrafenib showed promising activity, with an independently confirmed ORR of 41%, and was well tolerated in this population with recurrent or progressive BRAF V600–mutant pLGG, comparing favorably to historical data.

Clinical trial identification

Regulatory Agency Identifying Number(s): IND No.: 117,989. EudraCT Number: 2012-001499-12. Release date: 24 July, 2012.

Legal entity responsible for the study

Supported by GlaxoSmithKline. Dabrafenib is an asset of Novartis AG as of 2 March 2015.


Supported by GlaxoSmithKline. Dabrafenib is an asset of Novartis AG as of 2 March 2015.


M.W. Kieran: Membership on Board of Directors or Advisory Committee: Novartis. E. Bouffet, D. Hargrave: Consultancy: Novartis. A. Broniscer, K. Cohen, J. Whitlock: Research Funding: Novartis. I. Dunkel: Consultancy: Bayer, BMS, Eisai, Pfizer. M. Russo: Employment: Novartis Equity Ownership: Novartis, GSK. L. Tseng: Employment: Novartis Pharmaceuticals. Q. Liu: Employment: Novartis Equity Ownership: Novartis. N. Nebot: Employment: Novartis. All other authors have declared no conflicts of interest.

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