Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1
Karin S. Walsh, Pamela L. Wolters, Brigitte C. Widemann, Allison del Castillo, Maegan Sady, Tess Inker, Marie Claire Roderick, Staci Martin, Mary Anne Toledo‐Tamula, Kari Struemph, Iris Paltin, Victoria Collier, Kathy Mullin, Michael J. Fisher, Roger J. Packer
Abstract
<h3>Background and Objectives</h3> Neurofibromatosis type 1 (NF1)-associated cognitive impairments carry significant lifelong morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of mitogen-activated protein kinase inhibitor (MEKi) treatment. <h3>Methods</h3> Fifty-nine patients with NF1 aged 5–27 years on an MEKi clinical trial treating plexiform neurofibroma underwent pretreatment and follow-up cognitive assessments over 48 weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were the primary outcomes. Group-level (paired <i>t</i> tests) and individual-level analyses (Reliable Change Index, RCI) were used. <h3>Results</h3> Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: <i>t</i><sub>(58)</sub> = 3.03, <i>p</i> = 0.004, <i>d</i> = 0.24; 48-week Metacognition Index: <i>t</i><sub>(39)</sub> = 2.70, <i>p</i> = 0.01, <i>d</i> = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ<sup>2</sup> = 11.95, <i>p</i> = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate (<i>p</i> > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ<sup>2</sup> = 8.36, <i>p</i> = 0.004, OR = 4.6, and 48-week χ<sup>2</sup> = 9.34, <i>p</i> = 0.004, OR = 5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than nonimpaired patients (24 weeks 46% vs 8%; χ<sup>2</sup> = 9.54, <i>p</i> = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ<sup>2</sup> = 7.50, <i>p</i> = 0.02, OR = 9.0). <h3>Discussion</h3> Our data show no evidence of neurotoxicity in 48 weeks of treatment with an MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.