FDA Approval Summary: Selumetinib for Plexiform Neurofibroma

Abstract

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma–related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51–79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit–risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

External control arms in oncology: current use and future directions

“…The required specifications of study design and analysis plan will vary by intended purpose of external control data and selected data source. As discussed earlier, external control data has previously been used in oncology marketing applications reviewed by the FDA to establish natural history of disease, with or without an established standard of care, provide descriptive information regarding the treatment effects of individual components of a combination treatment effect, or to provide supportive analyses of direct comparison to an experimental arm [23,24,25,26,27,28,29].…”

“…NF1 is a rare disease that occurs in approximately 1 in 3000 births. [23] PN is a benign tumor that The patient populations of these two external control data sources were small and heterogeneous, with dissimilarities to each other as well as the experimental arm of SPRINT Phase II Stratum 1 [26,27]. Both studies helped to confirm the occurrence of spontaneous regression was uncommon, such that observed responses in SPRINT were reasonably deemed the effect of treatment with selumetinib.…”

“…The external control data was considered supportive in understanding the natural history of NF1 with inoperable PN as it provided important clinical context for the observed response rate [26,27].…”

Resolution of the Expert council on the problems of diagnosis and treatment of patients with plexiform neurofibromas

“…Единственной существующей на настоящий момент опцией таргетной терапии ПНФ является препарат селуметиниб (МНН: селуметиниб) [52].…”

Integrative pan-cancer analysis of MEK1 aberrations and the potential clinical implications

“…For instance, the combination of highly selective inhibitors of MEK1/2, including trametinib, cobimetinib and binimetinib, and BRAF inhibitors have been served as the FDA-approved strategies for the treatment of BRAF V600E-mutant melanoma 14 . On April 10, 2020, selumetinib received FDA approval for pediatric patients with neurofibromatosis type 1, and they must be at least 2 years old, symptomatic and unable to surgery 15 . Moreover, Researches on other MEK1 inhibitors are also performing, such as PD-0325901, TAK-733 and Refametinib 11 .…”