Selumetinib decreased tumor volume and improved quality-of-life outcomes among children with inoperable plexiform neurofibromas associated with neurofibromatosis type 1, according to results from a phase 2 trial.

Neurofibromatosis 1 is a genetic disorder that results in the upregulation of the RAS pathway. A potential manifestation of the disease is the development of plexiform neurofibromas, benign peripheral-nerve sheath tumors associated with complications such as pain, disfigurement, and functional impairments.

Due to the involvement of the RAS pathway, inhibition of the MEK has been hypothesized as a potential treatment. Selumetinib is a selective MEK inhibitor that showed promising results against plexiform neurofibromas in a phase 1 trial. The purpose of this phase 2 study was to determine the antitumor efficacy and the effects of the medication on quality of life among children with plexiform neurofibromas.

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The trial enrolled children with neurofibromatosis type 1 who either demonstrated at least 1 neurofibroma-related complication or who were at risk of developing complications. The authors reported the results from 50 children in the first cohort, who had symptomatic, inoperable plexiform neurofibromas and who received selumetinib twice daily for 28-day cycles until disease progression or for a maximum of 2 years.

The primary endpoint was tumor response rates, and key secondary endpoints included duration of response, quality of life, physical functioning, pain, and toxicities.

At baseline, the median patient age was 10.2 years (range, 3.5 to 17.4) and the median number of neurofibroma-related complications was 3. The most common complications were disfigurement, motor dysfunction, and pain.

Selumetinib resulted in a partial response rate of 74% (95% CI, 60-85%) with a median time to initial response of 8 cycles (range, 4-20) and the median time to best response was 16 cycles (range, 4-36). At best response, the median change in neurofibroma volume was -27.9%.

The response was considered durable in 56% of patients, with the median duration of response not yet reached. The progression-free survival (PFS) was also not yet reached, but was 84% at 3 years.

Patient- and parent-reported quality-of-life metrics also showed clinically meaningful improvement after 1 year of selumetinib, including improvements reported by patients for pain (74%), motor dysfunction (56%), and overall quality of life (48%).

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The authors said that these results “are in stark contrast to the findings of the NCI [National Cancer Institute] natural-history study, in which most patients had disease progression.” In the NCI natural-history study, 78% of age-matched patients experienced an increase of at least 20% in tumor volume over 3 years, with 3-year PFS of 15%.

Most adverse events (AEs) were grade 1 to grade 2 gastrointestinal effects such as nausea, vomiting, or diarrhea, and asymptomatic creatinine phosphokinase level elevations. Dose reductions were required in 28% of patients due to AEs, and 10% discontinued treatment. There were no reports of cardiac or ocular toxicities.

The authors concluded that these results demonstrate that selumetinib treatment “resulted in neurofibroma shrinkage in the majority of patients and provided clinically meaningful benefit.”


Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas [published online March 18, 2020]. N Engl J Med. doi: 10.1056/NEJMoa1912735