Cincinnati Children's Hospital, Cincinnati, OH.
NCI, Center for Cancer Research, Bethesda, MD.
J Clin Oncol. 2021 Mar 1;39(7):797-806. doi: 10.1200/JCO.20.02220. Epub 2021 Jan 28.
Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis.
Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses.
Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings.
To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.
神经纤维瘤病 1 型（NF1）患者常发生丛状神经纤维瘤（PN），这可导致严重的发病率。我们对 MAPK/ERK 激酶抑制剂米哚妥林（PD-0325901）在 NF1 患者和无法手术的 PN 患者中进行了 II 期试验。主要目标是基于体积磁共振成像分析的反应率。
纳入标准包括年龄≥16 岁且 PN 呈进行性或导致显著发病率。进行了首次剂量药代动力学研究。患者完成了患者报告的结果测量。患者每天口服米哚妥林两次，剂量为 2mg/m/剂量（最大剂量为每天两次 4mg），每 3 周用药 1 周停药。每个疗程持续 4 周。第一年每 4 个疗程进行评估，然后每 6 个疗程进行评估。患者最多可接受 24 个总疗程。
19 名患者入组，所有 19 名患者均接受了米哚妥林治疗。中位年龄为 24 岁（范围为 16-39 岁）；中位基线肿瘤体积为 363.8ml（范围为 3.9-5161ml）。19 名患者中有 8 名（42%）在第 12 个疗程时达到目标 PN 的部分缓解，10 名（53%）疾病稳定。1 名患者（5%）在第 8 个疗程时出现疾病进展。疼痛评分显著且持久下降。
据我们所知，这一分析代表了米哚妥林在 NF1 和 PN 患者中的活性和药代动力学的首次特征描述，也是 MAPK/ERK 激酶抑制剂在 NF1 和 PN 成人患者中首次发表的反应研究。米哚妥林每天两次以 2mg/m/剂量（最大剂量为 4mg）给药，每 3 周用药 1 周停药，结果显示部分缓解率为 42%，初步证据表明疼痛减轻。
