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Ceritinib in ALK-Rearranged Non-Small-Cell Lung Cancer

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Authors
Shaw, Alice T.; Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S. W.; Felip, Enriqueta; Chow, Laura Q. M.; Camidge, D. Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.
Issue Date
2014-03
Citation
New England Journal of Medicine, Vol.370 No.13, pp.1189-1197
Abstract
BackgroundNon-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. MethodsIn 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. ResultsA 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). ConclusionsCeritinib 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.) Ceritinib is 20 times as potent as crizotinib at inhibiting anaplastic lymphoma kinase (ALK) in vitro. In patients, ceritinib produced antitumor responses in 56% of those who had resistance to crizotinib. Genetic alterations in the anaplastic lymphoma kinase gene (ALK) are implicated in the pathogenesis of several human cancers.(1) ALK can be aberrantly activated by mutation, gene amplification, or chromosomal rearrangement, leading to the expression of a potent oncogenic driver. In non-small-cell lung cancer (NSCLC), ALK rearrangement occurs in approximately 5% of cases.(2)-(8)ALK-rearranged tumors depend on ALK for growth and survival and show marked sensitivity to ALK inhibitors such as crizotinib. Among patients with advanced, ALK-rearranged NSCLC, crizotinib has been associated with response rates of approximately 60% across multiple studies and a median progression-free survival ...
ISSN
0028-4793
URI
http://hdl.handle.net/10371/165428
DOI
https://doi.org/10.1056/NEJMoa1311107
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College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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