NEJM:Tepotinib在NSCLC中的MET Exon 14跳跃突变中的疗效与安全性

2020-06-12 MedSci MedSci原创

在全球范围内,肺癌是最常见的癌症类型,也是癌症死亡的首要原因,每年确诊200万例,死亡170万例。MET信号通路改变(包括MET第14号外显子跳跃突变和MET扩增)已在多种类型癌症中被发现,包括NSC

在全球范围内,肺癌是最常见的癌症类型,也是癌症死亡的首要原因,每年确诊200万例,死亡170万例。MET信号通路改变(包括MET第14号外显子跳跃突变和MET扩增)已在多种类型癌症中被发现,包括NSCLC,这与肿瘤的侵袭行为和不良的临床预后相关。据估计,MET信号通路改变发生在3-5%的NSCLC患者中。
 
美国食品和药物管理局(FDA)已授予其靶向抗癌药——口服MET抑制剂tepotinib突破性药物资格(BTD),用于治疗接受含铂化疗后病情进展、携带MET基因第14号外显子跳跃突变(MET exon14-skipping)的转移性非小细胞肺癌(NSCLC)患者。去年3月,tepotinib被日本卫生劳动福利部(MHLW)授予了治疗携带MET基因第14号外显子跳跃突变的晚期NSCLC患者的SAKIGAKE资格(创新药物)。

非小细胞肺癌(NSCLC)患者中,剪接位点突变导致致癌驱动因子MET中第14外显子的转录丢失。我们评估了高选择性MET抑制剂tepotinib在该患者人群中的疗效和安全性。

tepotinib是默克内部发现的一种口服MET激酶抑制剂,可强效、高度选择性抑制由MET(基因)改变——包括MET第14号外显子跳跃突变、MET扩增或MET蛋白过表达引起的致癌信号,具有改善携带这些特定MET改变的侵袭性肿瘤患者治疗预后的潜力。除了NSCLC之外,默克也正在积极评估tepotinib联合新疗法治疗其他肿瘤适应症。
tepotinib分子结构式(图片来源:chemicalbook.com)

在这项开放标签的2期研究中,我们对确诊的MET外显子14跳跃突变的晚期或转移性NSCLC患者每天一次给予tepotinib(剂量为500 mg)。主要终点是接受至少9个月随访的患者通过独立数据委员会评估客观反应率(ORR)。还根据在液体活检或组织活检中是否检测到MET外显子14跳跃突变的存在进行分析。

截至2020年1月1日,总共152例患者接受了tepotinib,其中99例患者接受了至少9个月的随访。独立数据委员会评估的ORR为46%(联合活检组的中位应答持续时间为11.1个月。液体活检组的有效率为48%,有活检组为50%。组织活检组60例,两种方法均阳性,研究者评估的缓解率为56%,无论是否接受晚期或转移性疾病的治疗均相似,均为3级或更高的不良事件据报道,有28%的患者被研究者认为与tepotinib治疗相关,包括7%的外周水肿;不良事件导致tepotinib永久性停药的患者为11%。在基线和治疗期间,在67%的患者对应的液体活检样本的患者中观察到游离DNA。

在患有确诊的MET外显子14跳跃突变的晚期NSCLC患者中,使用tepotinib与大约一半患者的部分缓解相关。周围水肿是3级或更高级别的主要毒性作用。

原始出处:

Paul K. Paik, et al. Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. NEJM, May 29, 2020 DOI: 10.1056/NEJMoa2004407

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    2021-03-24 一闲
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    2020-06-12 内科新手

    谢谢梅斯提供这么好的信息,学到很多

    0

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    2020-06-12 旺医

    顶刊就是顶刊,谢谢梅斯带来这么高水平的研究报道,我们科里同事经常看梅斯,分享梅斯上的信息

    0

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    2020-06-12 肿肿

    NSCLC下一步突破在于新靶点了,靶向治疗和免疫治疗基本见顶了,再有新的就需要新机制了

    0

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