Kwak, E. L., Bang, Y. J., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. H., Dezube, B. J., Janne, P. A., Costa, D. B., Varella-Garcia, M., Kim, W. H., Lynch, T. J., Fidias, P., Stubbs, H., Engelman, J. A., Sequist, L. V., Tan, W., Gandhi, L., Mino-Kenudson, M., Wei, G. C., Shreeve, S. M., Ratain, M. J., Settleman, J., Christensen, J. G., Haber, D. A., Wilner, K., Salgia, R., Shapiro, G. I., Clark, J. W., Iafrate, A. J. (October 2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 363 (18). pp. 1693-703. ISSN 1533-4406 (Electronic)0028-4793 (Linking)
Abstract
BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Administration, Oral Adult Aged Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology Cell Cycle Proteins/genetics Disease Progression Female Humans In Situ Hybridization, Fluorescence Kaplan-Meier Estimate Lung Neoplasms/*drug therapy/genetics/pathology Male Microtubule-Associated Proteins/genetics Middle Aged Mutation Oncogene Proteins, Fusion/genetics Protein Kinase Inhibitors/administration & dosage/adverse effects/*therapeutic use Protein-Tyrosine Kinases/*antagonists & inhibitors/genetics Proto-Oncogene Proteins c-met/antagonists & inhibitors Pyrazoles/administration & dosage/adverse effects/*therapeutic use Pyridines/administration & dosage/adverse effects/*therapeutic use Receptor Protein-Tyrosine Kinases Receptors, Growth Factor/antagonists & inhibitors Serine Endopeptidases/genetics |
| Subjects: | diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > lung cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Maki lab |
| Depositing User: | Matt Covey |
| Date: | 28 October 2010 |
| Date Deposited: | 21 Oct 2016 20:03 |
| Last Modified: | 21 Oct 2016 20:03 |
| PMCID: | PMC3014291 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33710 |
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