Selumetinib for Inoperable Plexiform Neurofibromas in Children With Neurofibromatosis Type 1

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In a phase II trial reported in The New England Journal of Medicine, Gross et al found that the oral MEK inhibitor selumetinib produced a high response rate and durable responses in children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas.

Study Details

The study, conducted at four sites in the United States, involved 50 children age 3.5 to 17.4 (median age = 10.2 years) who were treated with selumetinib at 25 mg/kg twice daily on a continuous schedule in 28-day cycles. Patients had a median of three neurofibroma-related complications, with the most common being disfigurement (n = 44), motor dysfunction (n = 33), and pain (n = 26). Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). Partial response was defined as a reduction in target neurofibroma volume of ≥ 20% from baseline.


Patients received a median of 36 cycles of treatment.


  • Confirmed responses were observed in 70% of patients.
  • Clinically meaningful improvements were observed in pain intensity, interference of pain in daily functioning, overall health-related quality of life, strength, and range of motion.

A total of 37 patients (74%) had partial response, and 35 (70%) had confirmed partial response. Median time to response was eight cycles of treatment. Response persisting for ≥ 1 year was observed in 28 patients (56%). The median change in neurofibroma volume at best response was -27.9% (range = −55.1% to 2.2%). Median duration of response and median progression-free survival were not reached; 3-year progression-free survival was 84%.

After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was two points, representing a clinically meaningful improvement. Proportions of children and parents reporting clinically meaningful improvements were 38% and 50% for interference of pain in daily functioning and 48% and 58% for overall health-related quality of life, respectively. Clinically meaningful improvements in the outcomes of strength and range of motion were reported by 56% and 38% of children.

Adverse Events

The most common adverse events were grade 1 or 2 gastrointestinal symptoms consisting of nausea, vomiting, and diarrhea; asymptomatic increases in creatine phosphokinase level; acneiform rash; and paronychia. Adverse events considered possibly related to treatment resulted in treatment discontinuation in five patients (10%), including grade 3 diarrhea, grade 3 weight gain, grade 3 paronychia, grade 4 skin ulceration, and grade 4 elevated creatinine level.

The investigators concluded, “In this phase II trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib.”

Disclosure: The study was supported by the Intramural Research Program of the National Institutes of Health, AstraZeneca, and others. For full disclosures of the study authors, visit

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