Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer

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)

URL: https://www.ncbi.nlm.nih.gov/pubmed/20979469
DOI: 10.1056/NEJMoa1006448

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: http://repository.cshl.edu/id/eprint/33710

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