Back to Search
Start Over
Ceritinib in ALK-rearranged non-small-cell lung cancer.
- Source :
-
The New England journal of medicine [N Engl J Med] 2014 Mar 27; Vol. 370 (13), pp. 1189-97. - Publication Year :
- 2014
-
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.<br />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.<br />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).<br />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.).
- Subjects :
- Adult
Aged
Aged, 80 and over
Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung mortality
Female
Humans
Lung Neoplasms genetics
Lung Neoplasms mortality
Male
Maximum Tolerated Dose
Middle Aged
Protein Kinase Inhibitors adverse effects
Protein Kinase Inhibitors pharmacokinetics
Pyrimidines adverse effects
Pyrimidines pharmacokinetics
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Recombination, Genetic
Sulfones adverse effects
Sulfones pharmacokinetics
Treatment Outcome
Young Adult
Carcinoma, Non-Small-Cell Lung drug therapy
Drug Resistance, Neoplasm genetics
Lung Neoplasms drug therapy
Protein Kinase Inhibitors administration & dosage
Pyrimidines administration & dosage
Receptor Protein-Tyrosine Kinases genetics
Sulfones administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4406
- Volume :
- 370
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- The New England journal of medicine
- Publication Type :
- Academic Journal
- Accession number :
- 24670165
- Full Text :
- https://doi.org/10.1056/NEJMoa1311107