PMID- 36884302
OWN - NLM
STAT- MEDLINE
DCOM- 20230727
LR  - 20230804
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 7
IP  - 15
DP  - 2023 Aug 8
TI  - Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated 
      pediatric Langerhans cell histiocytosis.
PG  - 3806-3815
LID - 10.1182/bloodadvances.2022008414 [doi]
AB  - Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder 
      primarily affecting children. BRAF mutations have been reported in >50% of 
      patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with 
      the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600-mutant 
      solid tumors. Two open-label phase 1/2 studies were conducted in pediatric 
      patients with BRAF V600-mutant, recurrent/refractory malignancies treated with 
      dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib 
      (CTMT212X2101; NCT02124772). The primary objectives of both studies were to 
      determine safe and tolerable doses that achieve similar exposure to the approved 
      doses for adults. Secondary objectives included safety, tolerability, and 
      preliminary antitumor activity. Thirteen and 12 patients with BRAF V600-mutant 
      LCH received dabrafenib monotherapy and in combination with trametinib, 
      respectively. Investigator-assessed objective response rates per Histiocyte 
      Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% 
      (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. 
      More than 90% of responses were ongoing at study completion. The most common 
      treatment-related adverse events (AEs) were vomiting and increased blood 
      creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil 
      count, and vomiting with combination therapy. Two patients each discontinued 
      treatment with monotherapy and combination therapy because of AEs. Overall, 
      dabrafenib monotherapy or in combination with trametinib demonstrated clinical 
      efficacy and manageable toxicity in relapsed/refractory BRAF V600-mutant 
      pediatric LCH, with most responses ongoing. Safety was consistent with that 
      reported in other pediatric and adult conditions treated with dabrafenib plus 
      trametinib.
CI  - (c) 2023 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Whitlock, James A
AU  - Whitlock JA
AUID- ORCID: 0000-0002-7887-0634
AD  - Department of Paediatrics, The Hospital for Sick Children/University of Toronto, 
      Toronto, ON, Canada.
FAU - Geoerger, Birgit
AU  - Geoerger B
AD  - Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, 
      Villejuif, France.
FAU - Dunkel, Ira J
AU  - Dunkel IJ
AUID- ORCID: 0000-0001-8091-6067
AD  - Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Roughton, Michael
AU  - Roughton M
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Choi, Jeea
AU  - Choi J
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ.
FAU - Osterloh, Lisa
AU  - Osterloh L
AD  - Novartis Farmaceutica SA, Barcelona, Spain.
FAU - Russo, Mark
AU  - Russo M
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ.
FAU - Hargrave, Darren
AU  - Hargrave D
AD  - UCL Great Ormond Street Institute for Child Health, London, United Kingdom.
LA  - eng
SI  - ClinicalTrials.gov/NCT01677741
SI  - ClinicalTrials.gov/NCT02124772
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - DH_/Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - QGP4HA4G1B (dabrafenib)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - 33E86K87QN (trametinib)
SB  - IM
MH  - Adult
MH  - Child
MH  - Humans
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - *Histiocytosis, Langerhans-Cell
PMC - PMC10393756
COIS- Conflict-of-interest disclosure: J.A.W. reports research funding (to institution) 
      from Novartis, consulting fees/participation in a data safety monitoring board 
      with Pfizer, and consulting fees/participation in advisory boards for Jazz 
      Pharmaceuticals. I.J.D. reports contracts (with institution) from Bristol Myers 
      Squibb, Genentech, and Novartis; payment (to institution) for role as chair of 
      the Pediatric Brain Tumor Consortium; consulting fees/participation in a data 
      safety monitoring board with Celgene/Bristol Myers Squibb; and consulting 
      fees/participation in advisory boards for AstraZeneca, Bristol Myers Squibb, Day 
      One, Fennec, QED, and Roche. J.C. and L.O. report employment with Novartis. M. 
      Russo and M. Roughton report stock/shares in and employment with Novartis. D.H. 
      reports consulting fees from Novartis and participation in a data safety 
      monitoring or advisory board for activities relating to trametinib and 
      dabrafenib. B.G. declares no competing financial interests.
EDAT- 2023/03/09 06:00
MHDA- 2023/07/27 06:42
PMCR- 2023/03/11
CRDT- 2023/03/08 12:03
PHST- 2023/02/25 00:00 [accepted]
PHST- 2022/06/24 00:00 [received]
PHST- 2023/07/27 06:42 [medline]
PHST- 2023/03/09 06:00 [pubmed]
PHST- 2023/03/08 12:03 [entrez]
PHST- 2023/03/11 00:00 [pmc-release]
AID - 494825 [pii]
AID - 10.1182/bloodadvances.2022008414 [doi]
PST - ppublish
SO  - Blood Adv. 2023 Aug 8;7(15):3806-3815. doi: 10.1182/bloodadvances.2022008414.