European Medicines Agency, Amsterdam, The Netherlands.
Committee for Medicinal Products for Human Use (CHMP), Amsterdam, The Netherlands.
Oncologist. 2020 Jul;25(7):e1070-e1076. doi: 10.1634/theoncologist.2019-0976. Epub 2020 Mar 10.
On October 24, 2019, a marketing authorization valid through the European Union (EU) was issued for gilteritinib monotherapy for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3 internal tandem duplication (ITD), FLT3 D835Y, and FLT3 ITD D835Y, and it induced apoptosis in leukemic cells expressing FLT3 ITD. The recommended starting dose of gilteritinib is 120 mg (three 40 mg tablets) once daily. Gilteritinib was evaluated in one, phase III, open-label, multicenter, randomized study of gilteritinib (n = 247, gilteritinib arm) versus salvage chemotherapy (n = 124, salvage chemotherapy arm) in patients with relapsed or refractory AML with FLT3 mutation. Overall survival (OS) was statistically significantly different between the two groups with a median OS of 9.3 months in the gilteritinib arm compared with 5.6 months for salvage chemotherapy (hazard ratio, 0.637; 95% confidence interval, 0.490-0.830; p = .0004 one-sided log-rank test). The most common adverse reactions with gilteritinib treatment were blood creatine phosphokinase increase, alanine aminotransferase increase, aspartate aminotransferase increase, blood alkaline phosphatase increase, diarrhea, fatigue, nausea, constipation, cough, peripheral edema, dyspnea, dizziness, hypotension, pain in extremity, asthenia, arthralgia, and myalgia. The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Xospata was approved in the European Union as monotherapy for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib resulted in a clinically meaningful and statistically significant improvement of overall survival compared with salvage chemotherapy. At the time of the marketing authorization of gilteritinib, there were no approved standard therapies specifically for adult patients diagnosed with relapsed or refractory AML with FLT3 mutation. In terms of safety, the overall accepted safety profile was considered manageable.
2019 年 10 月 24 日，一种在欧盟（EU）有效的营销授权被发放给了吉特替尼单药治疗，适用于有 Fms 样酪氨酸激酶 3（FLT3）突变的复发或难治性急性髓系白血病（AML）的成年患者。吉特替尼抑制细胞外表达 FLT3 的细胞中的 FLT3 受体信号和增殖，包括 FLT3 内部串联重复（ITD）、FLT3 D835Y 和 FLT3 ITD D835Y，并且它诱导表达 FLT3 ITD 的白血病细胞凋亡。吉特替尼的推荐起始剂量为 120mg（三粒 40mg 片剂），每日一次。在一项单臂、三期、开放性、多中心、随机研究中，评估了吉特替尼（n=247，吉特替尼组）与挽救化疗（n=124，挽救化疗组）在有 FLT3 突变的复发或难治性 AML 患者中的疗效。与挽救化疗相比，吉特替尼组的总生存期（OS）在统计学上有显著差异，吉特替尼组的中位 OS 为 9.3 个月，而挽救化疗组为 5.6 个月（风险比，0.637；95%置信区间，0.490-0.830；p=0.0004 单侧对数秩检验）。吉特替尼治疗最常见的不良反应是血肌酸磷酸激酶升高、丙氨酸氨基转移酶升高、天门冬氨酸氨基转移酶升高、血碱性磷酸酶升高、腹泻、疲劳、恶心、便秘、咳嗽、外周水肿、呼吸困难、头晕、低血压、肢体疼痛、乏力、关节痛和肌痛。本文的目的是总结导致在欧盟获得监管批准的科学审查。对实践的意义：Xospata 在欧盟被批准作为单药治疗有 Fms 样酪氨酸激酶 3（FLT3）突变的复发或难治性急性髓系白血病（AML）的成年患者。与挽救化疗相比，吉特替尼在总生存期方面取得了具有临床意义和统计学意义的改善。在吉特替尼获得营销授权时，没有专门针对诊断为有 FLT3 突变的复发或难治性 AML 的成年患者的批准标准疗法。在安全性方面，总体上可接受的安全性概况被认为是可控的。
