Targeting BRAF

Not all BRAF alterations can be targeted with type 1 BRAF inhibitors11

Ayiden, lives with pLGG.
Lives for basketball.

Targeting aberrant MAPK pathway signaling with BRAF and/or MEK inhibitors is a potential treatment option for patients with pediatric low-grade glioma (pLGG) harboring a BRAF alteration (fusion or mutation).1

Comparison of BRAF mutation and fusion inhibition from type 1 BRAF inhibitors
Comparison of BRAF mutation and fusion inhibition from type 1 BRAF inhibitors

Type 1 BRAF inhibitors inhibit MAPK signaling for V600E point mutations. However, they cannot inhibit signaling for BRAF fusions and have been shown to increase signaling.11

Type 1 BRAF inhibitors paradoxically activate MAPK signaling12

In the presence of wild-type RAF and RAF fusions, currently available BRAF inhibitors (type 1) may paradoxically activate MAPK signaling. This may increase the risk of cutaneous side effects, such as11,12:

  • Keratoacanthomas

  • Cutaneous squamous cell carcinomas

Advances in our understanding of the role of BRAF in pLGG suggest the need for novel therapies that specifically target both BRAF fusions and mutations, which together are the main underlying genomic drivers of the disease.1,2,11,12

Targeted RAF inhibition for pLGG13,14

There is ongoing clinical research into targeted RAF inhibition of both BRAF fusions and point mutations as a novel therapeutic strategy for patients with BRAF-altered pLGG.

Talk to your patients about early comprehensive BRAF testing in pLGG

Download the Discussion Guide

In tumors with BRAF fusions, currently available BRAF inhibitors (type 1) are not appropriate due to early evidence of overactive growth.7,8,10,15

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Treatment Challenges

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Cancers (Basel). 2019;11(9):1262. doi:10.3390/cancers11091262 7. Tafinlar® [Package Insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; 2022. 8. Braftovi® [Package Insert]. Boulder, CO: Array BioPharma, Inc.; 2022. 9. Koselugo® [Package Insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 10. Zelboraf® [Package Insert]. South San Francisco, CA: Genentech, Inc.; 2020. 11. Yaeger R, Corcoran RB. Targeting alterations in the RAF-MEK pathway. Cancer Discov. 2019;9(3):329-341. doi:10.1158/2159-8290.CD-18-1321 12. Holderfield M, Nagel TE, Stuart DD. Mechanism and consequences of RAF kinase activation by small-molecule inhibitors. Br J Cancer. 2014;111(4):640-645. doi:10.1038/bjc.2014.139 13. Wright K, Krzykwa E, Greenspan L, et al. EPCT-01 Phase I study of DAY101 (TAK580) in children and young adults with radiographically recurrent or progressive low-grade glioma (LGG). Neuro Oncol. 2020;22(Suppl 3):iii304. doi:10.1093/neuonc/noaa222.126 14. Drilon AE, Liu H, Wu F. Tumor-agnostic precision immuno-oncology and somatic targeting rationale for you (TAPISTRY): a novel platform umbrella trial. J Clin Oncol. 2021;39:15_suppl. doi:10.1200/JCO.2021.39.15_suppl.TPS3154 15. Karajannis MA, Legault G, Fisher MJ, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 2014;16(10):1408-1416. doi:10.1093/neuonc/nou059 16. Armstrong GT, Conklin HM, Huang S, et al. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol. 2011;13(2):223-234. doi:10.1093/neuonc/noq178 17. Heitzer AM, Raghubar K, Ris MD, et al. Neuropsychological functioning following surgery for pediatric low-grade glioma: a prospective longitudinal study. J Neurosurg Pediatr. 2019;1-9. doi:10.3171/2019.9.PEDS19357 18. Shortman RI, Beringer A, Penn A, Malson H, Lowis SP, Sharples PM. The experience of mothers caring for a child with a brain tumour. 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Lancet Oncol. 2019;20(7):1011-1022. doi:10.1016/S1470-2045(19)30277-3 24. Bouffet E, Whitlock JA. Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: safety and efficacy results. J Clin Oncol. 2020;38(15):10506-10506. doi:10.1200/JCO.2020.38.15_suppl.10506 25. Tsai JW, Choi JJ, Ouaalam H, et al. Integrated response analysis of pediatric low-grade gliomas during and after targeted therapy treatment. Neuro Oncol Adv. 2023;5(1):1-12. doi:10.1093/noajnl/vdac182 26. Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009;24(11):1397-1408. doi:10.1177/0883073809342005 27. Wen PY, Chang SM, Van den Bent MJ, et al. Response Assessment in Neuro-Oncology Clinical Trials. J Clin Oncol. 2017;35(1):2439-2449. doi:10.1200/JCO.2017.72.7511 28. Fangusaro J, Witt O, Driever PH, et al. Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. Lancet Oncol. 2020;21:e305-e316. 29. Chukwueke UN, Wen PY. Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice. CNS Oncol. 2019;8(1):1-16. doi:10.2217/cns-2018-0007