Selumetinib in Children with Inoperable Plexiform Neurofibromas

N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18.


Background: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.

Methods: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).

Results: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.

Conclusions: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; number, NCT01362803.).

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Benzimidazoles / adverse effects
  • Benzimidazoles / therapeutic use*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Male
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Nausea / chemically induced
  • Neurofibroma, Plexiform / complications
  • Neurofibroma, Plexiform / drug therapy*
  • Neurofibroma, Plexiform / pathology
  • Neurofibromatosis 1 / complications
  • Neurofibromatosis 1 / drug therapy*
  • Neurofibromatosis 1 / pathology
  • Pain / etiology
  • Patient Reported Outcome Measures
  • Progression-Free Survival
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Tumor Burden / drug effects


  • AZD 6244
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase Kinases

Associated data