History
Selumetinib was discovered by Array BioPharma and was licensed to AstraZeneca. It has been investigated for the treatment of various types of cancer, such as non-small cell lung cancer (NSCLC) and thyroid cancer.[19][20]
The US Food and Drug Administration (FDA) granted the application for selumetinib priority review, breakthrough therapy, and orphan drug designations.[12] It was granted a rare pediatric disease designation for the treatment of pediatric NF-1 along with a rare pediatric disease priority review voucher.[12] In April 2020, selumetinib was approved by the FDA for the treatment of children with NF-1.[21][22][23] It is the first drug approved in the US to treat this rare disease.[12]
The approval was based on a clinical trial[24] of children who had NF-1 and inoperable plexiform neurofibromas (defined as a PN that could not be completely removed without risk for substantial morbidity to the child), conducted by the National Cancer Institute.[12][22] The efficacy results were from 50 of the children who received the recommended dose and had routine evaluations of changes in tumor size and tumor-related morbidities during the trial.[12] The children received selumetinib 25 mg/m2 orally twice a day until disease progression or until they experienced unacceptable adverse reactions.[12][22] The clinical trial measured the overall response rate (ORR), defined as the percentage of subjects with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.[12]
Other clinical outcomes for subjects during selumetinib treatment included changes in PN-related disfigurement, symptoms and functional impairments.[12] Although the sample sizes of subjects assessed for each PN-related morbidity (such as disfigurement, pain, strength and mobility problems, airway compression, visual impairment and bladder or bowel dysfunction) were small, there appeared to be a trend of improvement in PN-related symptoms or functional deficits during treatment.[12]
Efficacy was evaluated in KOMET (NCT04924608), a global, randomized, multi-center, double-blind, placebo-controlled trial.[16] Eligible participants were required to be 18 years of age or older with NF1 and symptomatic, inoperable plexiform neurofibromas.[16] Inoperable plexiform neurofibroma was defined as a plexiform neurofibroma that could not be completely removed without risk for substantial morbidity due to encasement or close proximity to vital structures, invasiveness, or high vascularity.[16] A total of 145 participants were randomized (1:1) to selumetinib or placebo twice daily for twelve cycles.[16]
