Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer.
Kwak, Eunice L. M.D., Ph.D.; Bang, Yung-Jue M.D., Ph.D.; Camidge, Ross D. M.D., Ph.D.; Shaw, Alice T. M.D., Ph.D.; Solomon, Benjamin M.B., B.S., Ph.D.; Maki, Robert G. M.D., Ph.D.; Ou, Sai-Hong I. M.D., Ph.D.; Dezube, Bruce J. M.D.; Janne, Pasi A. M.D., Ph.D.; Costa, Daniel B. M.D., Ph.D.; Varella-Garcia, Marileila Ph.D.; Kim, Woo-Ho M.D.; Lynch, Thomas J. M.D.; Fidias, Panos M.D.; Stubbs, Hannah M.S.; Engelman, Jeffrey A. M.D., Ph.D.; Sequist, Lecia V. M.D., M.P.H.; Tan, WeiWei Ph.D.; Gandhi, Leena M.D., Ph.D.; Mino-Kenudson, Mari M.D.; Wei, Greg C. Ph.D.; Shreeve, Martin S. M.D., Ph.D.; Ratain, Mark J. M.D.; Settleman, Jeffrey Ph.D.; Christensen, James G. Ph.D.; Haber, Daniel A. M.D., Ph.D.; Wilner, Keith Ph.D.; Salgia, Ravi M.D., Ph.D.; Shapiro, Geoffrey I. M.D., Ph.D.; Clark, Jeffrey W. M.D.; Iafrate, John A. M.D., Ph.D.
[Article]
New England Journal of Medicine.
363(18):1693-1703, October 28, 2010.
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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.)
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