Crizotinib in ROS1-rearranged non-small-cell lung cancer.
Crizotinib in ROS1-rearranged non-small-cell lung cancer.
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DOI：
10.1056/nejmoa1406766
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发表时间：
2014-11-20
期刊：
影响因子：
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通讯作者：
Iafrate AJ
中科院分区：
文献类型：
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作者：
Shaw AT;Ou SH;Bang YJ;Camidge DR;Solomon BJ;Salgia R;Riely GJ;Varella-Garcia M;Shapiro GI;Costa DB;Doebele RC;Le LP;Zheng Z;Tan W;Stephenson P;Shreeve SM;Tye LM;Christensen JG;Wilner KD;Clark JW;Iafrate AJ
编码 ROS1 原癌基因受体酪氨酸激酶 (ROS1) 的基因的染色体重排定义了非小细胞肺癌 (NSCLC) 的一个独特分子亚组，可能对治疗性 ROS1 激酶抑制敏感。 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)。我们在克唑替尼 1 期研究的扩展队列中招募了 50 名 ROS1 重排检测呈阳性的晚期 NSCLC 患者。患者接受标准口服剂量克唑替尼（250 mg，每日两次）治疗，并评估安全性、药代动力学和治疗反应。使用下一代测序或逆转录酶聚合酶链反应测定来鉴定 ROS1 融合伴侣。客观缓解率为 72%（95% 置信区间 [CI]，58 至 84），其中 3 例完全缓解，33 例部分缓解。中位缓解持续时间为 17.6 个月（95% CI，14.5 至未达到）。中位无进展生存期为 19.2 个月（95% CI，14.4 至未达到），其中 25 名患者 (50%) 仍在随访病情进展。在测试的 30 个肿瘤中，我们鉴定了 7 个 ROS1 融合伴侣：5 个已知的伴侣基因和 2 个新的伴侣基因。 ROS1 重排类型与克唑替尼临床反应之间没有观察到相关性。克唑替尼的安全性与 ALK 重排 NSCLC 患者的安全性相似。在这项研究中，克唑替尼在晚期 ROS1 重排 NSCLC 患者中显示出显着的抗肿瘤活性。 ROS1 重排定义了克唑替尼具有高度活性的 NSCLC 的第二个分子亚型。
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. 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. 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. 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.