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腾讯登录NEJM：克唑替尼疗法或可有效阻断ROS1阳性的肺癌的恶化
| 导读 | 近日，发表在国际杂志New England Journal of Medicine上的一篇研究论文中，来自麻省总医院的研究人员通过研究发现，克唑替尼疗法可以有效抑制ROS1阳性的肺癌的发展，ROS1阳性肺癌即是由ROS1基因重排所诱发的肺癌。 |
近日，发表在国际杂志New England Journal of Medicine上的一篇研究论文中，来自麻省总医院的研究人员通过研究发现，克唑替尼疗法可以有效抑制ROS1阳性的肺癌的发展，ROS1阳性肺癌即是由ROS1基因重排所诱发的肺癌。
Alice Shaw博士表示，在该研究之前已经有很多研究都揭示了克唑替尼疗法对ROS1阳性肺癌的效应；而本文研究首次确定了克唑替尼疗法的确可以有效抑制ROS1阳性肺癌的发展，并且研究者指出ROS1或许就是开发肺癌疗法的一个新型靶点。目前克唑替尼是FDA批准的用于治疗非小细胞肺癌的一种新型药物，本文研究中，研究者招募了50名ROS1阳性的非小细胞肺癌患者进行1期临床试验，患者进行2倍剂量的克唑替尼进行治疗，结果发现患者机体的肿瘤尺寸明显降低了72%，而且肿瘤生长速度也降低了18%，该疗法的平均响应时间为17个月，在研究结束时，50名患者中有25名患者仍然没有得到克唑替尼疗法对肿瘤发展影响的一些证据。
研究者Shaw表示，几乎所有进行靶向性癌症疗法治疗的患者最终都会产生耐受性，而克唑替尼疗法对ROS1阳性的肺癌患者进行治疗的耐药性出现却发生地非常迟，而该疗法给患者带来的有益作用的时间也显得比一般疗法要长。研究者表示，有效的实验室诊断技术的开发对于鉴别ROS1基因的重排及其它驱动癌症发生的遗传改变非常关键，本文研究是癌症个体化疗法的一个成功例子。
非小细胞肺癌的发生是由于ALK基因的重排所致，虽然目前FDA批准的克唑替尼疗法仅覆盖ALK阳性的非小细胞肺癌患者中，研究者指出，国立癌症中心的指导准则或许将会推荐恶性肺癌患者也进行ROS1的检测及进行克唑替尼的疗法来治疗疾病。（转化医学网360zhyx.com）
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Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer
NEJM DOI: 10.1056/NEJMoa1311107
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.
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.
Full Text of Background...
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.
Full Text of Methods...
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).
Full Text of Results...
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.)
Full Text of Discussion...
NEJM DOI: 10.1056/NEJMoa1311107
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.
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.
Full Text of Background...
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.
Full Text of Methods...
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).
Full Text of Results...
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.)
Full Text of Discussion...
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