Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma

Abstract

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).

Keywords: Café-au-Lait spots; mitogen-activated protein kinase kinases; neurofibroma; neurofibromatosis 1; plexiform.

Figure 1.

Study flow diagram.

Figure 2.

Changes in tumor volume. (A) Percentage changes in the targeted tumor volume in each patient divided according to the number of cycles received. The dotted line denotes the threshold for partial response, which was defined as ≥20% reduction in tumor volume. *One child showed no response with an increased volume change of 0.7%. (B) Percentage changes in the targeted tumor volume in pediatric and adult patients according to the drug dosage. Each graph represents the mean and standard error of the means of each group. (C) Regular MRI scans of representative patients at baseline, cycle 12, and cycle 26. Left panel: an 8-year-old child in group 1. Right panel: a 34-year-old female 6 in group 3 (arrows, target lesion).

Figure 3.

Effects of selumetinib on Neurocognitive function, growth parameter, and café-au-lait spots. (A) Proportion of children (n = 54) and adult (n = 30) patients with normal (blue), borderline (orange), or intellectual disability (ID; red) at baseline and cycle 12 according to VCI, PRI, WMI, PSI, and FSIQ scores. (B) Cognitive functioning ratings of 44 patients at baseline, cycle 12, and cycle 26. Mean ± S.E. *P < .05 versus baseline. *P < .05 versus baseline. (C) Standard deviation (SD) scores of heights and growth velocity of 37 prepubertal patients at baseline, cycle 12, and cycle 26. Mean ± S.D. *P < .05 versus baseline. (D) Representative images of patients who showed improvements in café-au-lait spots. Intensity score of Café au lait spots Mean ± S.D. *P < .05 versus baseline. VCI, verbal comprehension index; PRI, perceptual reasoning index; WMI, working memory index; PSI, processing speed index; FSIQ, Full-Scale IQ.

Figure 4.

Effects of selumetinib on quality of life and pain. (A) Number of pediatric patients, their parents, and adult patients who reported improvements (blue), no change (orange), or worsening (gray) in their quality of life between baseline and cycle 26. Total scores and subscores (ie, school, social, emotional, and physical functioning) of quality of life are shown. (B) Duration of pain during the last 24 hours in adult patients. (C) Frequency of pain during the last 24 hours in adult patients. (D) Radial charts showing the scores of 5 fields (tumor volume, QOL score, pain score, FSIQ, processing speed) that were assessed at baseline, first evaluation, and second evaluation.