To investigate the survival advantage associated with MEK inhibitor (MEKi) therapy in patients with neurofibromatosis type 1 (NF1) associated high-grade glioma (HGGs).

NF1, a tumor predisposition syndrome, promotes gliomagenesis in a heterogeneous spectrum, from low- to high-grade, at any age. Low- and HGGs both exhibit different molecular features and outcomes. While some studies have shown promising efficacy of selumetinib on NF1-associated low-grade glioma, the effect of MEKi remained largely unknown in HGGs.

We conducted a retrospective review for all patients diagnosed with NF1 and HGG between 2019-2025, treated with MEKi for at least 28 days at MDACC. Each cycle consisted of 28 days.

Eight patients were identified, 4 females and 4 males. Age of onset for HGG was 33 years (range: 22-59). NF1-associated HGGs consisted of high-grade astrocytoma with pilocytic features (HGAP, N=6) and glioblastoma (GBM, N=2). NF1 mutation was identified in all the patients. For HGAP, the most frequent molecular alteration was ATRX mutation (N=6) followed by CDKN2A/B loss (N=2), whereas BRAF, TERT, TP53, and NOTCH3 mutations were identified in GBM. Six patients received MEKi after tumor progression from previous radiation therapy. While the duration of MEKi therapy was variable (range: 1-6 cycles) the PFS using MEKi was 3 months for HGAP and 2.5 months for GBM. Two HGAP and two GBM patients discontinued MEKi due to complications unrelated to treatment. The OS was 24.9 months for HGAP and 37.5 months for GBM. Three HGAP patients are currently alive at 6, 9, and 10 months from initial diagnosis; two on active treatment with MEKi.