Abstract
Purpose
The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation.
Methods
Thirty-six patients with NF1 (age range 3–19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change.
Results
Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes.
Conclusion
These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.
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References
Lammert M et al (2005) Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 141(1):71–74
Wang Y et al (2012) ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell 150(4):816–830
Hyman SL, Shores A, North KN (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65(7):1037–1044
Payne JM et al (2013) Paired associate learning in children with neurofibromatosis type 1: implications for clinical trials. J Neurol 260(1):214–220
Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14(3):311–317
Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5(3):173–183
Ribeiro MJ et al (2015) Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1. Cortex 64:194–208
Lacroix A et al (2022) Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1. Neurobiol Dis 174:105881
Violante IR et al (2016) GABA deficiency in NF1: a multimodal [11C]-flumazenil and spectroscopy study. Neurology 87(9):897–904
Kim KB et al (2013) Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 31(4):482
Blumenschein G Jr et al (2015) A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC). Ann Oncol 26(5):894–901
Dombi E et al (2016) Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N Engl J Med 375(26):2550–2560
Gross AM et al (2020) Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med 382(15):1430–1442
Mueller S et al (2020) NFB-17. Mek inhibitor binimetinib shows clinical activity in children with neurofibromatosis type 1- associated plexiform neurofibromas: a report from pnoc and the nf clinical trials consortium. Neuro Oncol 22(Suppl 3): p 420–1
Perreault S et al (2019) A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01. BMC Cancer 19(1):1–9
Perreault S et al (2021) Syst-04. tram-01: a phase 2 study of trametinib for patients with pediatric glioma with activation of the mapk/erk pathway. Neuro-Oncology Advances 3(Supplement_4):iv9–iv9
Weiss BD et al (2021) NF106: a neurofibromatosis clinical trials consortium phase II trial of the MEK inhibitor mirdametinib (PD-0325901) in adolescents and adults with NF1-related plexiform neurofibromas. J Clin Oncol 39(7):797–806
Borrie SC et al (2021) MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders. Mol Autism 12(1):53
Walsh KS et al (2021) Impact of MEK inhibitor therapy on neurocognitive functioning in NF1. Neurol Genet 7(5): p e616
Legius E et al (2021) Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med 23(8): p 1506–1513
Delis DC, Kaplan E, Kramer JH, Delis-Kaplan executive function system (D-KEFS). (2001) San Antonio, TX: San Antonio. The Psychological Corporation, TX
Field A (2013) Discovering statistics using IBM SPSS statistics (4th ed.). London, England : SAGE Publications.
Dugan JA, Bauer PJ (2022) Putting the pieces together: Cognitive correlates of self-derivation of new knowledge in elementary school classrooms. J Exp Child Psychol 221:105441
Acknowledgements
Mélanie Alves for her support during the preparation of this manuscript.
Funding
Funding for this study came from the Canadian Institute Health Research (S.P., S.L.), Association de la Neurofibromatose du Québec (S.L.) and the Fondation du Grand défi Pierre Lavoie (S.L.), Fonds de Recherche en Santé du Québec (S.L., E.L., S.P.).
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E.L., S.L. and S.P. wrote the main manuscript text. E.L. prepared the figures and tables. All authors reviewed the manuscript.
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Lalancette, E., Cantin, É., Routhier, MÈ. et al. Impact of trametinib on the neuropsychological profile of NF1 patients. J Neurooncol (2024). https://doi.org/10.1007/s11060-024-04624-3
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DOI: https://doi.org/10.1007/s11060-024-04624-3