New Oral Therapy Shows Promise Against Neurofibromatosis Type 1-Related Plexiform Neurofibromatomas in Children

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Long-term dose-adjusted selumetinib may be beneficial for pediatric neurofibromatosis type 1.
Long-term dose-adjusted selumetinib may be beneficial for pediatric neurofibromatosis type 1.

Early-phase clinical trial data suggest treatment with long-term dose-adjusted selumetinib is beneficial for children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas, a study presented in The New England Journal of Medicine has shown.1

Neurofibromatosis type 1 is a common genetic disorder often diagnosed in childhood, with most rapid tumor growth occurring prior to adolescence. Approximately 50% of people with NF1 develop plexiform neurofibromas, which are characterized by elevated RAS–mitogen-activated protein kinase (MAPK) signaling.

Complete surgical resection is rarely practical, and incomplete resection of tumors tends to result in regrowth. Therefore, researchers sought to determine the toxicity and safety of selumetinib, a selective inhibitor of the MEK protein, in children.

For the clinical trial ( Identifier: NCT01362803), researchers enrolled 24 children, 11 girls and 13 boys, age 3 to 18.5 years (median, 10.9 years) with a median tumor volume of 1205 ml (range, 29 to 8744 ml). The participants received 20 to 30 mg/m2 twice daily on a continuous dosing schedule in 28-day cycles. Median number of cycles received was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg/m2.

In addition, researchers tested selumetinib using a mouse model of NF1-related neurofibroma. Volumetric MRI was used to monitor the change in volume of plexiform neurofibroma.

Confirmed partial response, defined as a reduction in tumor volume of 20% or greater from baseline, was achieved in 71% (17) of the children. Decreased neurofibroma volume was noted in 67% (12 of 18) mice. Anecdotal evidence of reductions in tumor-related pain, disfigurement, and functional impairment were observed. Disease progression, defined as an increase in tumor volume of 20% or greater from baseline, has not been observed to date.

Most patients continue to receive selumetinib, in some cases for as long as 5 years. Long-term treatment has had no adverse effects to date on the participants' development of overall health.

A loss of response with slow regrowth of tumors was observed in some patients, particularly after dose reductions, and the researchers suggest studies to characterize tumors that no longer respond to selumetinib are warranted. The National Cancer Institute, which sponsored this trial, is also sponsoring an ongoing trial of selumetinib in adults with NF1. A larger phase II pediatric trial is also underway.


1. Dombi E, Baldwin A, Marcus LJ, et al. Activity of selemetinib in neurofibromatosis type 1–related plexiform neurofibromas. N Engl J Med. 2016 Dec 29. doi: 10.1056/NEJMoa1605943. [epub ahead of print]

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