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

  • N Engl J Med. 2010 Oct 28;363(18):1693-703. doi: 10.1056/NEJMoa1006448.
Eunice L Kwak  1 ,  Yung-Jue Bang ,  D Ross Camidge ,  Alice T Shaw ,  Benjamin Solomon ,  Robert G Maki ,  Sai-Hong I Ou ,  Bruce J Dezube ,  Pasi A Jänne ,  Daniel B Costa ,  Marileila Varella-Garcia ,  Woo-Ho Kim ,  Thomas J Lynch ,  Panos Fidias ,  Hannah Stubbs ,  Jeffrey A Engelman ,  Lecia V Sequist ,  WeiWei Tan ,  Leena Gandhi ,  Mari Mino-Kenudson ,  Greg C Wei ,  S Martin Shreeve ,  Mark J Ratain ,  Jeffrey Settleman ,  James G Christensen ,  Daniel A Haber ,  Keith Wilner ,  Ravi Salgia ,  Geoffrey I Shapiro ,  Jeffrey W Clark ,  A John Iafrate
Affiliations
  • 1. Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. [email protected]
PMID: 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.).