Efficacy and safety of MEK inhibitors for NF1-associated symptomatic, inoperable plexiform neurofibromas: A systematic review and meta-analysis
- 1Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, University of Chicago, Chicago, Illinois, United States of America
- 2Division of Pediatric Neurology, University of Chicago, Chicago, Illinois, United States of America
Abstract
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.
Related
- Cardiac Myosin Inhibitors in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials
- From MEK inhibition to rational combination strategies for NF1-associated plexiform neurofibromas
- Efficacy of sodium-glucose cotransporter-2 inhibitors on functional mitral regurgitation associated with heart failure: a systematic review and meta-analysis of randomized controlled trials
- Immune-related adverse events are associated with favorable clinical outcomes in esophageal cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis.
- Dramatic response of an inoperable Merkel cell carcinoma with imatinib
BibTeX
@article{damodharan2026efficacy,
title = {{Efficacy and safety of MEK inhibitors for NF1-associated symptomatic, inoperable plexiform neurofibromas: A systematic review and meta-analysis}},
author = {Sudarshawn Damodharan and James Tonsgard},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359957},
url = {https://doi.org/10.1371/journal.pone.0359957},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Efficacy and safety of MEK inhibitors for NF1-associated symptomatic, inoperable plexiform neurofibromas: A systematic review and meta-analysis
AU - Sudarshawn Damodharan
AU - James Tonsgard
PY - 2026
DA - 2026/10/06
JO - PLOS One
DO - 10.1371/journal.pone.0359957
UR - https://doi.org/10.1371/journal.pone.0359957
AB - 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.
SN - 1932-6203
ER -