塞瑞替尼治疗间变性淋巴瘤激酶重排的非小细胞肺癌。
Ceritinib in ALK-rearranged non-small-cell lung cancer.
机构信息
From Massachusetts General Hospital, Boston (A.T.S., J.A.E.); Seoul National University Hospital, Seoul, South Korea (D.-W.K.); Fox Chase Cancer Center, Philadelphia (R.M.); National Cancer Center and Genome Institute of Singapore, Singapore (D.S.W.T.); Vall d'Hebron University, Barcelona (E.F.); University of Washington, Seattle (L.Q.M.C.); University of Colorado, Denver (D.R.C.); University Hospital KU Leuven, Leuven, Belgium (J.V.); Huntsman Cancer Institute, Salt Lake City (S.S.); Istituto Europeo di Oncologia (T.D.P.) and Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas (A.S.) - both in Milan; Memorial Sloan-Kettering Cancer Center, New York (G.J.R.); Peter MacCallum Cancer Center, Melbourne, VIC, Australia (B.J.S.); Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg, German Center for Lung Research (M.T.), and German Cancer Consortium (M.S.), Heidelberg, and University Duisburg-Essen, Essen (M.S.) - all in Germany; Princess Margaret Cancer Center, Toronto (G.L.); and Novartis Institutes for BioMedical Research, Cambridge, MA (Y.Y.L., M.G., A.L.B.).
出版信息
N Engl J Med. 2014 Mar 27;370(13):1189-97. doi: 10.1056/NEJMoa1311107.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.).
背景
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，但耐药性不可避免。塞瑞替尼（LDK378）是一种新型的 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活性。
方法
在这项 I 期研究中，我们给患有 ALK 基因改变的晚期癌症患者口服塞瑞替尼，剂量为 50 至 750mg，每日一次。在研究的扩展阶段，患者接受了最大耐受剂量。评估患者的安全性、药代动力学特性和塞瑞替尼的抗肿瘤活性。在一组接受克唑替尼治疗后疾病进展的 NSCLC 患者中，在开始塞瑞替尼治疗前进行肿瘤活检，以鉴定 ALK 中的耐药突变。
结果
共有 59 名患者入组剂量递增阶段。塞瑞替尼的最大耐受剂量为每日 750mg；剂量限制毒性事件包括腹泻、呕吐、脱水、转氨酶水平升高和低磷血症。随后进入扩展阶段，又有 71 名患者接受了治疗，共有 130 名患者。在 114 名至少接受 400mg 塞瑞替尼/天的 NSCLC 患者中，总体缓解率为 58%（95%置信区间[CI]，48 至 67）。在 80 名之前接受过克唑替尼治疗的患者中，缓解率为 56%（95%CI，45 至 67）。在具有各种 ALK 耐药突变的患者和未检测到突变的患者中均观察到了应答。在至少接受 400mg 塞瑞替尼/天的 NSCLC 患者中，中位无进展生存期为 7.0 个月（95%CI，5.6 至 9.5）。
结论
塞瑞替尼对晚期、ALK 重排的 NSCLC 患者具有高度活性，包括那些在克唑替尼治疗期间疾病进展的患者，无论 ALK 中是否存在耐药突变。（由诺华制药公司等资助；ClinicalTrials.gov 编号，NCT01283516。）
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