Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study

Souichi Suenobu; Keita Terashima; Masaharu Akiyama; Tomoyo Oguri; Asako Watanabe; Masatoshi Sugeno; Mitsuo Higashimori; Karen So; Yoshihiro Nishida

doi:10.1093/noajnl/vdad054

Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study

Neurooncol Adv. 2023 May 23;5(1):vdad054. doi: 10.1093/noajnl/vdad054. eCollection 2023 Jan-Dec.

Authors

Souichi Suenobu¹, Keita Terashima², Masaharu Akiyama³, Tomoyo Oguri⁴, Asako Watanabe⁴, Masatoshi Sugeno⁴, Mitsuo Higashimori⁴, Karen So⁵, Yoshihiro Nishida⁶

Affiliations

¹ Department of Pediatrics, Oita University Hospital, Yufu, Japan.
² Division of Neuro-Oncology, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
³ Department of Pediatrics, The Jikei University Hospital, Tokyo, Japan.
⁴ Research and Development, AstraZeneca K.K., Osaka, Japan.
⁵ Alexion, AstraZeneca Rare Disease Clinical Development, NF and Bone Metabolism Therapeutic Area, Cambridge, UK.
⁶ Department of Orthopedic Surgery, Nagoya University Hospital, Nagoya, Japan.

Abstract

Background: Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase I study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN.

Methods: Eligible patients (aged 3-18 years) received oral selumetinib (25 mg/m² twice daily) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL.

Results: Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cutoff: cycle 13 day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration and area under the concentration-time curve from time 0-6 hours.

Conclusions: Consistent with results of the phase II SPRINT trial, 25 mg/m² selumetinib twice daily was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN.

Keywords: MEK inhibitor; Neurofibromatosis 1; plexiform neurofibroma; selumetinib.