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.
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.
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.
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 nejm.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.