Disease Stabilization with MEK Inhibitors in NF1-Associated Plexiform Neurofibromas: A Systematic Review and Meta-Analysis with Subgroup Analyses by Age and Study Design.
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BACKGROUND: Plexiform neurofibromas (PN) represent a significant cause of morbidity among patients diagnosed with neurofibromatosis type 1 (NF1). MEK inhibitors continue to be developed as targeted therapies by inhibiting the mitogen-activated protein kinase pathway to treat PN; nonetheless to this day, therapeutic responses have varied across different patient populations and clinical contexts, and the overall efficacy and tolerability of these agents remain incompletely characterized. OBJECTIVE: We aimed to systematically evaluate the efficacy and safety of MEK inhibitor therapy in patients with NF1-associated PN and to evaluate differences among key subgroups based on the most contemporary metadata. METHODS: A comprehensive search was performed across electronic databases to identify studies that reported outcomes related to MEK inhibitor therapy in NF1-associated PN. Pooled proportions were calculated using a random-effects meta-analysis with logit transformation. Outcomes assessed included objective response rate, disease control rate, disease progression rate, and grade ≥ 3 adverse events. RESULTS: A total of 23 studies comprising 769 patients were included. The pooled objective response rate was estimated at 56% (95% confidence interval [CI] 46-65; I2 = 79.2%), with significantly higher response rates observed in clinical trials (61%) compared with real-world cohorts (44%) [p = 0.035], while no statistically significant difference was observed between pediatric (58%) versus adult populations (51%) [p = 0.407]. The pooled disease control rate was 96% (95% CI 91-98; I2 = 17%) and the pooled disease progression rate was estimated at 2% (95% CI 1-5; I2 = 0%), both reflecting on-treatment outcomes. Grade ≥ 3 adverse events occurred in 13% of patients (95% CI 6-25; I2 = 51.9%). Subgroup analyses revealed comparable disease control across study settings, with moderate variability in response and toxicity estimates. CONCLUSIONS: The use of MEK inhibitors is associated with high rates of disease control and minimal tumor progression in patients with NF1-related PN, with consistent effects observed across clinical trial and real-world environments. Although tumor reduction occurs in some patients, the predominant therapeutic benefit appears to be sustained disease stabilization, with response variability noted among different age groups and study designs.