Treatment decisions and the use of MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas

Amy E Armstrong; Allan J Belzberg; John R Crawford; Angela C Hirbe; Zhihong J Wang

doi:10.1186/s12885-023-10996-y

Treatment decisions and the use of MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas

BMC Cancer. 2023 Jun 16;23(1):553. doi: 10.1186/s12885-023-10996-y.

Authors

Amy E Armstrong¹, Allan J Belzberg², John R Crawford^{3

4}, Angela C Hirbe⁵, Zhihong J Wang⁶

Affiliations

¹ Division of Pediatric Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, USA. armstrongae@wustl.edu.
² Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ CHOC Neuroscience Institute, Children's Hospital of Orange County, Orange, CA, USA.
⁴ Department of Pediatrics, Division of Child Neurology University of California Irvine, Orange, CA, USA.
⁵ Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Division of Hematology and Oncology, Children's Hospital of Richmond, Virginia Commonwealth University, Richmond, VA, USA.

Abstract

Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.

Keywords: Clinical decision making; MEK inhibitors; Neurofibromatosis type 1; Plexiform neurofibroma; Surgery.

Publication types

Review

MeSH terms

Child
Humans
Mitogen-Activated Protein Kinase Kinases
Neurofibroma, Plexiform* / drug therapy
Neurofibromatosis 1* / complications
Neurofibromatosis 1* / drug therapy
Neurofibromatosis 1* / genetics
Protein Kinase Inhibitors / therapeutic use
Quality of Life

Substances

Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase Kinases