Abstract / Summary
Plexiform neurofibromas arise in up to half of people with neurofibromatosis type 1 (NF1), causing pain, disfigurement and functional loss. Loss of neurofibromin releases RAS-MAPK signaling, making MEK1/2 a rational target. Two agents are now approved in the United States, the adult indication only since 2025. We evaluated the efficacy and safety of MEK inhibitor monotherapy in NF1-associated symptomatic, inoperable plexiform neurofibroma across children and adults. We searched six databases and registries from inception to 10 July 2026, reporting per PRISMA 2020. The primary outcome was objective response rate (≥20% tumor volume reduction, REiNS criteria). Two reviewers screened, extracted and appraised studies (RoB 2, ROBINS-I); certainty was rated with GRADE. Proportions were pooled using random-effects models after Freeman-Tukey transformation, with subgrouping by age. Eleven reports of nine studies (528 participants) met eligibility, covering selumetinib, mirdametinib, trametinib and binimetinib. The pooled descriptive response rate was 53.7% (95% CI 40.5-66.6; I2 = 84.0%) and varied by age: 62.9% in children versus 40.8% in adults. Because eight of the nine strata were single-arm, these are descriptive pooled proportions rather than controlled treatment effects. Adult heterogeneity was driven almost entirely by KOMET, the only randomized trial (20% versus 5% with placebo, p = 0.011); excluding it, the adult estimate was 49.0%. Responses were partial but usually durable, with improvements in pain and quality of life. Toxicity was mostly low grade, with uncommon cardiac and ocular events. MEK inhibition shrinks symptomatic inoperable plexiform neurofibromas in children and adults and is now supported by randomized evidence, although pooled estimates represent a weighted average across four pharmacologically distinct agents rather than a single class effect. Benefit is partial and depends on continued treatment. Optimal duration, comparative effectiveness and any effect on malignant transformation remain undefined.