Plexiform neurofibromas in neurofibromatosis type 1: current and emergent therapeutic strategies

Abstract

Neurofibromatosis type 1-associated plexiform neurofibromas cause significant morbidity and carry a risk of malignant transformation. Early targeted agents failed to demonstrate efficacy, safety, or durable responses until the discovery of mitogen-activated protein kinase kinase (MEK 1/2) inhibitors. Selumetinib and mirdametinib are approved medical therapies that can potentially reduce tumor volume and symptoms, improve patient-reported outcomes, and have manageable toxicities. An indirect comparison between selumetinib and mirdametinib suggests differences in efficacy and safety, but direct confirmatory head-to-head trials are needed. Active clinical trials in the pipeline are exploring other targets in the MEK pathway, along with combination therapies. Key priorities include the impact of malignant peripheral nerve sheath tumor risk, defining long-term safety, durability off therapy, predictors of response and resistance, and implementation of multidisciplinary care.

Keywords

Neurofibromatosis type 1 / plexiform neurofibroma / mitogen-activated protein kinase kinase inhibitors / mitogen-activated protein kinase pathway / targeted therapy

References

[1] Hirbe AC.Neurofibromatosis type 1: a multidisciplinary approach to care.Lancet Neurol2014;13:834-43

[2] Fisher MJ,Weiss BD.Management of neurofibromatosis type 1-associated plexiform neurofibromas.Neuro Oncol2022;24:1827-44 PMCID:PMC9629437

[3] Na B,Vasudevan HN.Past, present, and future therapeutic strategies for NF-1-associated tumors.Curr Oncol Rep2024;26:706-13

[4] Weiss B,Wolters P.Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.Neuro Oncol2015;17:596-603 PMCID:PMC4483073

[5] Robertson KA,Yang FC.Pilot phase II trial of imatinib mesylate in neurofibromatosis type 1 patients with plexiform neurofibromas.Lancet Oncol2012;13:1218-24

[6] Widemann BC,Dombi E.Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.Pediatr Blood Cancer2014;61:1598-602 PMCID:PMC7681788

[7] Widemann BC,Gillespie A.Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.Neuro Oncol2014;16:707-18 PMCID:PMC3984559

[8] Shih CS. Study of sutent®/sunitinib (SU11248) in subjects with NF-1 plexiform neurofibromas; 2018. Available from: https://clinicaltrials.gov/study/NCT01402817 [Last accessed on 11 Feb 2026]

[9] Gorai S,Das K.Selumetinib-A comprehensive review of the new FDA-approved drug for neurofibromatosis.Indian Dermatol Online J2024;15:701-5 PMCID:PMC11265740

[10] Akbarzadeh M,Hosseini M.Mirdametinib approval for neurofibromatosis type 1 with inoperable plexiform neurofibromas: the journey of MEK inhibitors.ESMO Rare Cancers2025;3:100015

[11] Solares I,Morales-Conejo M,Feliu J.Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review.ESMO Open2021;6:100223 PMCID:PMC8363824

[12] Gross AM,Dombi E.Selumetinib in children with inoperable plexiform neurofibromas.N Engl J Med2020;382:1430-42

[13] FDA. FDA approves selumetinib for adults with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selumetinib-adults-neurofibromatosis-type-1-symptomatic-inoperable-plexiform [Last accessed on 11 Feb 2026]

[14] Chen AP,Wolters PL.Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): a multicentre, international, randomised, placebo-controlled, parallel, double-blind, phase 3 study.Lancet2025;405:2217-30

[15] Moertel CL,Shuhaiber HH.ReNeu: a pivotal, phase IIb trial of mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma.J Clin Oncol2025;43:716-29 PMCID:PMC11825507

[16] FDA. FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic [Last accessed on 11 Feb 2026]

[17] Mol I,Hu Y,Weber M.CO122 indirect treatment comparison (ITC) of mirdametinib and selumetinib for the treatment of children with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN).Value Health2025;28:S45

[18] Gross AM,Wolters PL.Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.Neuro Oncol2023;25:1883-94 PMCID:PMC10547508

[19] Healx Limited. A phase 2, open-label, single arm, non-controlled, single-stage study to evaluate the safety and effects of HLX-1502 in patients with plexiform neurofibroma and neurofibromatosis type 1 (INSPIRE-NF1). Available from: https://clinicaltrials.gov/study/NCT06541847 [Last accessed on 11 Feb 2026]

[20] Korf B. Phase II study of binimetinib in children and adults with NF1 Plexiform neurofibromas (NF108-BINI). Available from: https://clinicaltrials.gov/study/NCT03231306 [Last accessed on 11 Feb 2026]

[21] Fisher MJ,Rhodes SD.Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.Nat Med2021;27:165-73 PMCID:PMC8275010

[22] Dhall G. Study of cabozantinib with selumetinib for plexiform neurofibromas (NF113). Available from: https://clinicaltrials.gov/study/NCT06502171 [Last accessed on 11 Feb 2026]

[23] Sundby RT,Pan AC.Early detection of malignant and premalignant peripheral nerve tumors using cell-free DNA fragmentomics.Clin Cancer Res2024;30:4363-76

[24] Bai RY,Liu J.Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors.Nat Commun2025;16:8594 PMCID:PMC12480499

[25] Mueller S,Dombi E.NFB-17. MEK inhibitor binimetinib shows clinical activity in children with neurofibromatosis type 1- associated plexiform neurofibromas: a report from pnoc and the nf clinical trials consortium.Neuro Oncol2020;22:iii420-1 PMCID:PMC7715338

[26] Klesse LJ,Radtke HB.The use of MEK inhibitors in neurofibromatosis type 1-associated tumors and management of toxicities.Oncologist2020;25:e1109-16 PMCID:PMC7356675