Delgado J, Pean E, Melchiorri D, Migali C, Josephson F, Enzmann H, Pignatti F
Oncology and Haematology Office, European Medicines Agency, Amsterdam, The Netherlands; Department of Haematology, Hospital Clinic, Barcelona, Spain.
Oncology and Haematology Office, European Medicines Agency, Amsterdam, The Netherlands.
ESMO Open. 2021 Apr;6(2):100087. doi: 10.1016/j.esmoop.2021.100087. Epub 2021 Mar 16.
Entrectinib is an inhibitor of the tyrosine kinases TRKA, TRKB, TRKC [all together known as neurotrophic tyrosine receptor kinases (NTRKs)], ROS1 and anaplastic lymphoma kinase (ALK). On 31 July 2020, a conditional marketing authorisation valid through the European Union (EU) was issued for entrectinib for the treatment of adult and paediatric patients 12 years of age and older with NTRK fusion-positive solid tumours that are locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have not received a prior NTRK inhibitor and have no satisfactory therapy; and also for adult patients with ROS1-positive non-small-cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors. The submission was based on three open-label, multicentre, phase I studies (ALKA, STARTRK-1 and STARTRK-NG) and one phase II study (STARTRK-2). In patients with NTRK-positive solid tumours, the objective response rate (ORR) was 63.5% [95% confidence interval (CI) 51.5% to 74.4%] and the median duration of response (DOR) was 12.9 months (95% CI 9.3-not estimable). In patients with ROS1-positive NSCLC, the ORR was 67.1% (95% CI 59.25% to 74.27%) and the median DOR was 15.7 months (95% CI 13.9-28.6 months). The most frequent adverse events were dysgeusia, fatigue, dizziness, constipation, diarrhoea, nausea, increased weight, paraesthesia, increased creatinine, myalgia, peripheral oedema, vomiting, arthralgia, anaemia and increased AST. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval of entrectinib in the EU.
恩曲替尼是酪氨酸激酶TRKA、TRKB、TRKC（统称为神经营养性酪氨酸受体激酶，即NTRKs）、ROS1和间变性淋巴瘤激酶（ALK）的抑制剂。2020年7月31日，欧盟（EU）发布了恩曲替尼的有条件上市许可，用于治疗12岁及以上的成人和儿童患者，这些患者患有NTRK融合阳性实体瘤，局部晚期、转移性或手术切除可能导致严重并发症，且未接受过先前的NTRK抑制剂治疗且没有满意的治疗方案；也用于治疗先前未接受过ROS1抑制剂治疗的ROS1阳性非小细胞肺癌（NSCLC）成人患者。该申请基于三项开放标签、多中心、I期研究（ALKA、STARTRK-1和STARTRK-NG）和一项II期研究（STARTRK-2）。在NTRK阳性实体瘤患者中，客观缓解率（ORR）为63.5%[95%置信区间（CI）51.5%至74.4%]，中位缓解持续时间（DOR）为12.9个月（95%CI 9.3 - 不可估计）。在ROS1阳性NSCLC患者中，ORR为67.1%（95%CI 59.25%至74.27%），中位DOR为15.7个月（95%CI 13.9 - 28.6个月）。最常见的不良事件有味觉障碍、疲劳、头晕、便秘、腹泻、恶心、体重增加、感觉异常、肌酐升高、肌痛、外周水肿、呕吐、关节痛、贫血和AST升高。本手稿的目的是总结导致恩曲替尼在欧盟获得监管批准的申请的科学审评情况。
