ID #141 The Use of MEK Inhibitors for Neurofibromatosis Type 1-Associated High Grade Glioma and High-Grade Astrocytoma with Piloid Features in Children and Young Adults: A Real-World Cohort Analysis

Introduction Off-label use of MEK inhibitors for neurofibromatosis type 1-associated high grade glioma (NF1-HGG) is increasing, despite a paucity of supporting efficacy data. Methods Children and young adults with germline NF1 variants and a diagnosis of pathologic and/or molecularly confirmed HGG or methylation array-confirmed high-grade astrocytoma with piloid features (HGAP) treated with MEK inhibitor (MEKi) between 2005 to 2024 across 17 institutions were included. Retrospective clinical, molecular, and imaging data were analyzed. Results 27 subjects met inclusion criteria. The most prevalent diagnoses were high-grade astrocytoma (n = 10), HGAP (n = 9), and glioblastoma (n = 6). The median age at diagnosis was 14.3 years (range 2.7-33). Nineteen tumors had molecular sequencing at diagnosis: 63% were ATRX-altered, 58% were CDKN2A/B-altered, and 16% were TP53-altered. Two-year overall survival was 76% (95% CI 54,88). Seven subjects (26%) received MEKi as frontline therapy, the remaining 20 at recurrence. Median duration of treatment was 4 months (range 0.5-44) with MEKi monotherapy (n = 30), 5.5 months (1-18) for MEKi combined with bevacizumab (n = 8), and 6.5 months (1-16) for MEKi with other chemotherapy (n = 8); the median duration for bevacizumab monotherapy was 4 months (1-31) (n = 15). Duration of frontline MEKi therapy was 3 months (0.5-24) compared to 6 months (1-44) in relapsed/progressive setting (P = 0.187). Of the 9 subjects with durable response to MEKi (>12 months), 5 had HGAP and 2 had HGG with histology suspicious for HGAP without methylation confirmation; the remaining 2 subjects had HGG without methylation. No additional demographic, tumor, or treatment characteristics predicted durable response to MEKi. Conclusion Clinical response of NF1-HGG and HGAP to MEKi is highly variable and largely not sustained, highlighting the urgent need for effective therapies. The upcoming NF Clinical Trials Consortium study will prospectively evaluate prognostic factors for durable response to MEKi in NF1-HGG and HGAP. Central review of imaging response for this cohort is ongoing.