Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.
Hyery Kim, Hee Mang Yoon, Eun Key Kim, Young Shin Ra, Hyo-Won Kim, Mi-Sun Yum, Min-Jee Kim, Jae Suk Baek, Yu Sub Sung, Sang Min Lee, Hyeong-Seok Lim, Byung Joo Lee, Hyun Taek Lim, Dohyung Kim, Jihee Yoon, Hyunwoo Bae, Soojin Hwang, Yun-Ha Choi, Kyung Ah Kim, In Hee Choi, Seung Won Lee, Su-Jung Park, Beom Hee Lee
Author Information
Hyery Kim: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hee Mang Yoon: Department of Radiology and Research Institute of Radiology, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Eun Key Kim: Department of Plastic Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Young Shin Ra: Department of Neurosurgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hyo-Won Kim: Department of Psychiatry, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Mi-Sun Yum: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Min-Jee Kim: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jae Suk Baek: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Yu Sub Sung: Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Sang Min Lee: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hyeong-Seok Lim: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Byung Joo Lee: Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hyun Taek Lim: Orthopia Eye Clinic, Seoul, Republic of Korea.
Dohyung Kim: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jihee Yoon: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hyunwoo Bae: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Soojin Hwang: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Yun-Ha Choi: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Kyung Ah Kim: Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
In Hee Choi: Department of Genetic Counseling, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Seung Won Lee: Radiation Oncology Laboratory, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Su-Jung Park: School of Korean Medicine, Pusan National University, Pusan, Korea.
Beom Hee Lee: Orthopia Eye Clinic, Seoul, Republic of Korea. ORCID
BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1 manifestations (eg, neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase II trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hours for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22 ± 5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P < .05). Prepubertal patients showed increases in height score and growth velocity (P < .05). Café-au-lait spot intensity decreased significantly (P < .05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSIONS: Selumetinib decreases PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in nonmalignant diverse NF1 manifestations. TRIAL REGISTRATION: Cris.nih.go.kr Identifier (KCT0003700).
