Ceritinib in ALK-rearranged non-small-cell lung cancer.
Ceritinib in ALK-rearranged non-small-cell lung cancer.
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DOI：
10.1056/nejmoa1311107
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发表时间：
2014-03-27
期刊：
影响因子：
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通讯作者：
Engelman JA
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文献类型：
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作者：
Shaw AT;Kim DW;Mehra R;Tan DS;Felip E;Chow LQ;Camidge DR;Vansteenkiste J;Sharma S;De Pas T;Riely GJ;Solomon BJ;Wolf J;Thomas M;Schuler M;Liu G;Santoro A;Lau YY;Goldwasser M;Boral AL;Engelman JA
携带间变性淋巴瘤激酶基因（ALK）重排的非小细胞肺癌（NSCLC）对ALK抑制剂克唑替尼敏感，但不可避免地会产生耐药性。色瑞替尼（LDK378）是一种新的ALK抑制剂，在临床前研究中显示出比克唑替尼更强的抗肿瘤效力。
在这项1期研究中，我们对携带ALK基因改变的晚期癌症患者给予每日一次、剂量为50 - 750mg的口服色瑞替尼。在研究的扩展阶段，患者接受最大耐受剂量。对患者进行评估以确定色瑞替尼的安全性、药代动力学特性和抗肿瘤活性。在色瑞替尼治疗前对一组在克唑替尼治疗期间疾病进展的NSCLC患者进行肿瘤活检，以确定ALK中的耐药突变。
共有59名患者参与剂量递增阶段。色瑞替尼的最大耐受剂量为每日750mg；剂量限制性毒性事件包括腹泻、呕吐、脱水、转氨酶水平升高和低磷血症。该阶段之后是扩展阶段，又有71名患者接受治疗，总共130名患者。在114名每日至少接受400mg色瑞替尼的NSCLC患者中，总体缓解率为58%（95%置信区间[CI]，48 - 67）。在80名先前接受过克唑替尼治疗的患者中，缓解率为56%（95% CI，45 - 67）。在ALK有各种耐药突变的患者以及未检测到突变的患者中均观察到缓解。在每日至少接受400mg色瑞替尼的NSCLC患者中，中位无进展生存期为7.0个月（95% CI，5.6 - 9.5）。
色瑞替尼在晚期ALK重排的NSCLC患者中高度有效，包括那些在克唑替尼治疗期间疾病进展的患者，无论ALK是否存在耐药突变。（由诺华制药等资助；ClinicalTrials.gov编号，NCT01283516）
Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.)