NEJM：强效抗癌药ceritinib有效之治疗肺癌

诺华研发的Ceritinib是一种ALK抑制剂，体外试验显示，其ALK抑制效果和克里唑蒂尼比较要高出20倍。2014年3月27号NEJM发表了Ceritinib的临床1期研究结果：对克里唑蒂尼耐药的ALK-重排NSCLC患者，服用Ceritinib后所产生的治疗应答率高达56%。

原文摘要

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,

原始出处

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.Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer.N Engl J Med March 27, 2014