ROS1 fusion c-MET amplification c-MET-mutation crizotinib lung cancer targeted therapy
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摘要

BACKGROUND:In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC).
PATIENTS AND METHODS:Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance.
RESULTS:From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported.
CONCLUSIONS:Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.
CLINICAL TRIAL NUMBER:NCT02034981.

译文

背景: 2013,法国国家癌症研究所启动了 acs é 计划,为患者提供在其上市批准之外的安全靶向治疗。然后使用两阶段 Simon II 期试验设计评估疗效和安全性。当设计研究设计时,克唑替尼仅被批准作为成人间变性淋巴瘤激酶加非小细胞肺癌的单一疗法。
患者和方法: c-MET ≥ 6 拷贝、 c-MET 突变或 ROS-1-translocated 肿瘤的晚期非小细胞肺癌患者被纳入三个队列之一。患者接受克唑替尼 250 毫克每日两次治疗。使用两周期克唑替尼后的客观反应率 (ORR) 作为主要结果来评估疗效。次要结果包括四个周期的疾病控制率、最佳 ORR 、无进展生存期、总生存期和药物耐受性。
结果: 从 2013年8月到 2018年3月,5606 名患者接受了克唑替尼靶向分子改变的肿瘤检测: 252 名患者的 c-MET ≥ 6 拷贝,74 个 c-MET 突变, 和 78 ROS-1-translocated 爆炸。最后,c-MET ≥ 6 拷贝队列中的 25 名患者、 c-MET 突变队列中的 28 名患者和 ROS-1-translocation 队列中的 37 名患者在 II 期试验中得到治疗。在 c-MET ≥ 6 份的队列中,ORR 为 16%,突变组为 10.7%,ROS-1 组为 47.2%。治疗期间的最佳 ORR 在 c-MET ≥ 6 拷贝队列中为 32%,在 c-MET 突变队列中为 36%,在 ROS-1-translocation 队列中为 69.4%。安全数据与之前报道的一致。
结论: ROS1-translocated 肿瘤患者的克唑替尼活性得到证实。在 c-MET 突变和 c-MET ≥ 6 拷贝的队列中,尽管在克唑替尼的两个周期后 ORR 不足, 有晚期反应的迹象不足以证明克唑替尼在这一适应症中的发展是合理的。用创新疗法持续靶向 c-MET 似乎是合理的。
临床试验编号: nct02034981。

Crizotinib

肿瘤 肺癌 药物
概述  :  

克唑替尼,商品名叫Xalkori,赛可瑞。为粉红色硬胶囊剂,内容物为白色结晶粉末。是辉瑞制药研制的一种口服酪氨酸激酶受体抑制剂,在美国于2011年上市,用于治疗间变性淋巴瘤激酶(ALK)阳性的局部晚期和转移的非小细胞肺癌(NSCLC)。克唑替尼是酪氨酸激酶受体包括ALK、肝细胞生长因子受体(HGFR、c-Met)、ROS1和酪氨酸激酶(RON)的一种抑制剂。易位可影响ALK基因导致致癌融合蛋白的表达。ALK融合蛋白的形成导致激活和基因表达和增加细胞增殖有贡献信号的调节异常而生存肿瘤表达这些蛋

Crizotinib 

释    义   n. 克唑替尼(药物名称)

例    句   Crizotinib activity in patients with ROS1-translocated tumours was confirmed. 克唑替尼在ROS1易位肿瘤患者中的活性得到证实。

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