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 NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown.
METHODS: This open-label, phase 2 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 hrs 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 <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). 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 decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.
METHODS: This open-label, phase 2 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 hrs 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 <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). 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 decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.
摘要：
背景：MEK抑制剂，selumetinib,减少1型神经纤维瘤病（NF1）儿科患者的丛状神经纤维瘤（PN）。其在成人PN中的安全性和有效性以及在其他NF1表现中的有效性(例如，神经认知功能,增长减少，和咖啡馆的斑点）是未知的。
方法：这个开放标签，2期试验纳入了90名不可手术的儿童或成人NF1患者，症状,或者潜在的病态，可测量PN（≥3厘米）。塞美替尼以20或25mg/m2或50mg每12小时的剂量施用2年。药代动力学，PN体积,生长参数，神经认知功能,咖啡厅-au-lait斑点，和生活质量（QoL）进行评估。
结果：59名儿童和30名成人（中位年龄，16年；范围，3-47）平均接受22±5（4-26）个周期的司美替尼。89例符合方案的患者中有88例（98.9%）显示目标PN体积减少（中位数，40.8%；4.2%-92.2%），81例（91%）患者出现部分缓解（体积减少≥20%）。反应持续到第26周期。神经认知功能的分数(言语理解，感知推理，处理速度,和全面智商）在儿童和成人患者中均有显着改善（P<0.05）。青春期前患者身高评分和生长速度均增加(P<0.05)。Café-au-lait斑点强度显着降低（P<0.05）。儿童和成人均观察到QoL和疼痛评分的改善。所有不良事件均为CTCAE1级或2级，均成功治疗，未停药。
结论：Selumetinib减少了大多数儿童和成人NF1患者的PN体积，同时还显示了在非恶性多种NF1表现中的疗效。
方法：这个开放标签，2期试验纳入了90名不可手术的儿童或成人NF1患者，症状,或者潜在的病态，可测量PN（≥3厘米）。塞美替尼以20或25mg/m2或50mg每12小时的剂量施用2年。药代动力学，PN体积,生长参数，神经认知功能,咖啡厅-au-lait斑点，和生活质量（QoL）进行评估。
结果：59名儿童和30名成人（中位年龄，16年；范围，3-47）平均接受22±5（4-26）个周期的司美替尼。89例符合方案的患者中有88例（98.9%）显示目标PN体积减少（中位数，40.8%；4.2%-92.2%），81例（91%）患者出现部分缓解（体积减少≥20%）。反应持续到第26周期。神经认知功能的分数(言语理解，感知推理，处理速度,和全面智商）在儿童和成人患者中均有显着改善（P<0.05）。青春期前患者身高评分和生长速度均增加(P<0.05)。Café-au-lait斑点强度显着降低（P<0.05）。儿童和成人均观察到QoL和疼痛评分的改善。所有不良事件均为CTCAE1级或2级，均成功治疗，未停药。
结论：Selumetinib减少了大多数儿童和成人NF1患者的PN体积，同时还显示了在非恶性多种NF1表现中的疗效。
