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Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1
Karin S Walsh1, Pamela L Wolters1, Brigitte C Widemann1
1Children's National Medical Center (K.S.W., A.C., M.D.S., T.I., R.J.P.), Washington, DC; National Cancer Institute (P.L.W., B.C.W., M.C.R., S.M., K.S.), Bethesda, MD; Clinical Research Directorate (M.A.T.-T.), Frederick National Library for Cancer Research, MD; and Children's Hospital of Philadelphia (I.P., V.C., K.M., M.J.F.), Philadelphia.
Background And Objectives:
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.
Methods:
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 t tests) and individual-level analyses (Reliable Change Index, RCI) were used.
Results:
Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: t (58) = 3.03, p = 0.004, d = 0.24; 48-week Metacognition Index: t (39) = 2.70, p = 0.01, d = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ2 = 11.95, p = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate (p > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ2 = 8.36, p = 0.004, OR = 4.6, and 48-week χ2 = 9.34, p = 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%; χ2 = 9.54, p = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ2 = 7.50, p = 0.02, OR = 9.0).
Discussion:
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.
