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色瑞替尼治疗ALK重排非小细胞肺癌的临床研究
Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer


Alice T. Shaw ... 肿瘤 呼吸系统疾病 • 2014.03.27
相关阅读
• 对艾乐替尼和克唑替尼用于未经治疗的ALK阳性非小细胞肺癌的比较研究

摘要


背景

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,但最终总会产生耐药。色瑞替尼(LDK378)作为一种新型ALK抑制剂在临床前研究中呈现出比克唑替尼更优越的抗肿瘤活性。

 

方法

在这项一期临床研究中,携带ALK基因变异的晚期肿瘤患者接受色瑞替尼口服,每天1次,每次50~750 mg。在本试验的扩增阶段,患者接受最大耐受剂量的试验药物。该研究主要评价色瑞替尼的安全性、药代动力学特征及抗肿瘤活性。在接受色瑞替尼治疗前,克唑替尼治疗期间出现疾病进展的患者接受肿瘤活检以确认是否存在ALK耐药突变。

 

结果

共59例患者被纳入剂量递增期的研究。色瑞替尼的最大耐受剂量是750 mg;剂量限制性的毒性事件包括腹泻、呕吐、脱水、转氨酶的升高及低磷血症。在接下来的扩增期阶段,另外71位患者被纳入研究,参与整个试验的总人数为130人。其中114位NSCLC患者每天接受至少400 mg的色瑞替尼治疗,总体有效率58%(95%可信区间[CI],48~67)。既往接受过克唑替尼治疗的80位患者其色瑞替尼有效率为56%(95% CI,45~67)。色瑞替尼对不同ALK耐药突变患者及无法检测到突变的患者均有效。在每天接受至少400 mg色瑞替尼治疗的患者中,中位无进展生存期为7.0个月(95% CI,5.6~9.5)。

 

结论

ALK重排晚期NSCLC肿瘤患者中,包括在克唑替尼治疗期间出现疾病进展的患者中,色瑞替尼均有显著疗效;而且色瑞替尼的有效性不论NSCLC肿瘤是否存在ALK耐药基因突变(由诺华制药公司[Navartis Pharmaceuticals]等资助,ClinicalTrials.gov注册号为NCT01283516)。





作者信息

Alice T. Shaw, M.D., Ph.D., Dong-Wan Kim, M.D., Ph.D., Ranee Mehra, M.D., Daniel S.W. Tan, M.B., B.S., Enriqueta Felip, M.D., Ph.D., Laura Q.M. Chow, M.D., D. Ross Camidge, M.D., Ph.D., Johan Vansteenkiste, M.D., Ph.D., Sunil Sharma, M.D., Tommaso De Pas, M.D., Gregory J. Riely, M.D., Ph.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Juergen Wolf, M.D., Ph.D., Michael Thomas, M.D., Martin Schuler, M.D., Geoffrey Liu, M.D., Armando Santoro, M.D., Yvonne Y. Lau, Ph.D., Meredith Goldwasser, Sc.D., Anthony L. Boral, M.D., Ph.D., and Jeffrey A. Engelman, M.D., Ph.D.
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.). Address reprint requests to Dr. Shaw at the Massachusetts General Hospital Cancer Center, Yawkey 7B, 32 Fruit St., Boston, MA 02114, or at ashaw1@mgh.harvard.edu.

 

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