Impact of trametinib on the neuropsychological profile of NF1 patients

Eve Lalancette; Édith Cantin; Marie-Ève Routhier; Chantal Mailloux; Marie-Claude Bertrand; Dorsa Sadat Kiaei; Valérie Larouche; Uri Tabori; Cynthia Hawkins; Benjamin Ellezam; Jean-Claude Décarie; Yves Théoret; Marie-Élaine Métras; Tara McKeown; Luis H Ospina; Stéphanie Vairy; Vijay Ramaswamy; Hallie Coltin; Serge Sultan; Geneviève Legault; Éric Bouffet; Lucie Lafay-Cousin; Juliette Hukin; Craig Erker; Maxime Caru; Mathieu Dehaes; Nada Jabado; Sébastien Perreault; Sarah Lippé

doi:10.1007/s11060-024-04624-3

Impact of trametinib on the neuropsychological profile of NF1 patients

J Neurooncol. 2024 Mar 5. doi: 10.1007/s11060-024-04624-3. Online ahead of print.

Authors

Eve Lalancette¹, Édith Cantin², Marie-Ève Routhier², Chantal Mailloux³, Marie-Claude Bertrand³, Dorsa Sadat Kiaei⁴, Valérie Larouche⁵, Uri Tabori⁶, Cynthia Hawkins⁷, Benjamin Ellezam⁸, Jean-Claude Décarie⁹, Yves Théoret¹⁰, Marie-Élaine Métras¹⁰, Tara McKeown⁶, Luis H Ospina¹¹, Stéphanie Vairy¹², Vijay Ramaswamy⁶, Hallie Coltin¹³, Serge Sultan⁴, Geneviève Legault¹⁴, Éric Bouffet⁶, Lucie Lafay-Cousin¹⁵, Juliette Hukin¹⁶, Craig Erker¹⁷, Maxime Caru¹⁸, Mathieu Dehaes^{4

19}, Nada Jabado²⁰, Sébastien Perreault²¹, Sarah Lippé^{4

22}

Affiliations

¹ CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada. eve.lalancette.1@umontreal.ca.
² Division of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada.
³ Division of Neuropsychology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁴ CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁵ Division of Hemato-Oncology, Department of Pediatrics, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada.
⁶ Division of Hemato-Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.
⁷ Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
⁸ Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁹ Department of Radiology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹⁰ Department of Pharmacology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹¹ Department of Ophthalmology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹² Division of Hemato-Oncology, CHU Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹³ Department of Hemato-Oncology, CHU Sainte Justine, Université de Montréal, Montréal, QC, Canada.
¹⁴ Division of Neurology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montréal, QC, Canada.
¹⁵ Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.
¹⁶ Department of Pediatrics, Divisions of Neurology and Oncology, BC Children's Hospital, University of British Columbia, Vancouver, BCBC, Canada.
¹⁷ Division of Hemato-Oncology, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, NS, Canada.
¹⁸ Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children's Hospital, Hershey, PA, USA.
¹⁹ Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montréal, Montréal, Canada.
²⁰ Division of Hemato-Oncology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montréal, QC, Canada.
²¹ Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
²² Department of Psychology, Faculty of Arts and Sciences, University of Montréal, Montréal, Canada.

PMID: 38443693
DOI: 10.1007/s11060-024-04624-3

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.

Keywords: MEK inhibitor; Neurofibromatosis type 1; Neuropsychological profile; Trametinib.