目前肺癌的发病率持续上升,而靶向治疗既能提高治疗效果,又可以减少负作用,是目前研究的热点。最新研究发现,小分子酪氨酸激酶抑制剂Crizotinib,对原癌基因受体酪氨酸激酶(ROS1)基因发生染色体重排的非小细胞肺癌病人具有明显的抗肿瘤活性,ROS1重排也确定了继ALK重排后第二种Crizotinib有高度活性的NSCLC分子亚型。

—2014927日《新英格兰医学杂志》

 

中文翻译


 

【题目】Crizotinib 治疗ROS1重排的非小细胞肺癌

【译文】

背景:编码ROS1原癌基因受体酪氨酸激酶(ROS1)的基因发生染色体重排,定义了一种独特的非小细胞肺癌(NSCLC)亚群,该亚群可能对ROS1酶抑制剂治疗敏感。Crizotinib是一种小分子酪氨酸激酶抑制剂,可抑制间变性淋巴瘤激酶(ALK)、ROS1和另一种原癌基因受体酪氨酸激酶MET

方法:我们招募了50名进展期的NSCLC患者,他们在1Crizotinib研究的扩展队列中检测出ROS1重排阳性。这些病人按照Crizotinib标准剂量250mg2/天口服治疗,我们评价了药物安全性、药代动力学和对治疗的反应。我们使用新一代测序或逆转录聚合酶链反应检测法,来确定ROS1发生融合的病人。

结果:治疗的客观有效率为72%95%CI: 58-84),3个病人对治疗完全有效,33个病人有部分效果。疗效持续的中位时间为17.6个月(95%CI: 14.5-不可测)。中位无进展生存时间为19.2个月(95CI: 14.4-不可测),其中25个病人(50%)病情进展但仍在继续随访中。在30个可检测肿瘤的病人中,我们确定了7ROS1融合候选基因,包括5个已知基因和2个新发现基因。ROS1重排类型与Crizotinib临床效果之间未发现相关性。Crizotinib的安全性与在ALK重排的NSCLC病人中相似。

结论:在本研究中,CrizotinibROS1重排的NSCLC病人具有明显的抗肿瘤活性。ROS1重排确定了第二种Crizotinib有高度活性的NSCLC分子亚型。

 

英文原稿


 

[Title] Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer

[Authors] Alice T. Shaw, M.D., Ph.D., Sai-Hong I. Ou, M.D., Ph.D., Yung-Jue Bang, M.D., Ph.D.,
D. Ross Camidge, M.D., Ph.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Ravi Salgia, M.D., Ph.D.,
Gregory J. Riely, M.D., Ph.D., Marileila Varella-Garcia, Ph.D., Geoffrey I. Shapiro, M.D., Ph.D.,
\Daniel B. Costa, M.D., Ph.D., Robert C. Doebele, M.D., Ph.D., Long Phi Le, M.D., Ph.D.,
Zongli Zheng, Ph.D., Weiwei Tan, Ph.D., Patricia Stephenson, Sc.D., S. Martin Shreeve, M.D.,
Ph.D., Lesley M. Tye, Ph.D., James G. Christensen, Ph.D., Keith D. Wilner, Ph.D., Jeffrey W. Clark,
M.D., and A. John Iafrate, M.D., Ph.D.

[Abstract]

BACKGROUND: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor
tyrosine kinase (ROS1) define a distinct molecular subgroup of non–small-cell lung cancers (NSCLCs)
that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine
kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor
tyrosine kinase, MET.

METHODS: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1
rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with
crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics,
and response to therapy. ROS1 fusion partners were identified with the use of next-generation
sequencing or reverse-transcriptase–polymerase-chain-reaction assays.

RESULTS: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3
complete responses and 33 partial responses. The median duration of response was 17.6 months
(95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4
to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were
tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation
was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The
safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.

CONCLUSIONS: In this study, crizotinib showed marked antitumor activity in patients with advanced
ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC
for which crizotinib is highly active.

 

原文地址

http://www.nejm.org/doi/full/10.1056/NEJMoa1406766?query=featured_home#t=article

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