Ceritinib in ALK-rearranged non-small-cell lung cancer Journal Article


Authors: Shaw, A. T.; Kim, D. W.; Mehra, R.; Tan, D. S. W.; Felip, E.; Chow, L. Q. M.; Camidge, D. R.; Vansteenkiste, J.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B. J.; Wolf, J.; Thomas, M.; Schuler, M.; Liu, G.; Santoro, A.; Lau, Y. Y.; Goldwasser, M.; Boral, A. L.; Engelman, J. A.
Article Title: Ceritinib in ALK-rearranged non-small-cell lung cancer
Abstract: 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. Copyright © 2014 Massachusetts Medical Society.
Keywords: adult; cancer survival; controlled study; human tissue; treatment outcome; aged; aged, 80 and over; middle aged; survival rate; young adult; gene mutation; major clinical study; drug tolerability; advanced cancer; diarrhea; drug efficacy; drug safety; drug withdrawal; hypophosphatemia; progression free survival; lung non small cell cancer; nausea; vomiting; carcinoma, non-small-cell lung; lung neoplasms; dehydration; qt prolongation; gene function; tumor biopsy; drug resistance, neoplasm; pyrimidines; drug dose escalation; hyperglycemia; protein kinase inhibitors; oncogene; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; survival time; gene rearrangement; recombination, genetic; gene identification; drug response; cancer fatigue; clinical effectiveness; maximum tolerated dose; phase 1 clinical trial; receptor protein-tyrosine kinases; lung carcinogenesis; lung biopsy; amylase; sulfones; triacylglycerol lipase; blood level; anaplastic lymphoma kinase; molecular pathology; disease activity; hypertransaminasemia; crizotinib; alk gene; very elderly; humans; human; male; female; priority journal; article; ceritinib
Journal Title: New England Journal of Medicine
Volume: 370
Issue: 13
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2014-03-27
Start Page: 1189
End Page: 1197
Language: English
DOI: 10.1056/NEJMoa1311107
PUBMED: 24670165
PROVIDER: scopus
PMCID: PMC4079055
DOI/URL:
Notes: Cited By (since 1996):1 -- Export Date: 1 May 2014 -- CODEN: NEJMA -- Source: Scopus
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  1. Gregory J Riely
    605 Riely