| 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.) Copyright © 2010 Massachusetts Medical Society. |
| Keywords: |
adult; human tissue; treatment response; aged; middle aged; major clinical study; mutation; clinical trial; constipation; drug activity; fatigue; neutropenia; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypophosphatemia; recommended drug dose; side effect; treatment duration; pyridines; antineoplastic agent; adenocarcinoma; cell cycle proteins; gene; in situ hybridization, fluorescence; progression free survival; enzyme inhibition; multiple cycle treatment; lung non small cell cancer; nausea; carcinoma, non-small-cell lung; lung neoplasms; cancer screening; appetite; dizziness; drug dose escalation; lymphocytopenia; pneumonia; protein kinase inhibitors; hypoxia; lung embolism; kaplan-meiers estimate; correlation analysis; gene rearrangement; serine endopeptidases; disease progression; multicenter study; pyrazoles; oncogene proteins, fusion; peripheral edema; protein-tyrosine kinases; drug blood level; maximum tolerated dose; phase 1 clinical trial; tobacco; administration, oral; visual disorder; receptors, growth factor; anaplastic lymphoma kinase; 3 [1 (2,6 dichloro 3 fluorophenyl)ethoxy] 5 [1 (4 piperidinyl) 1h pyrazol 4 yl] 2 pyridinylamine; proto-oncogene proteins c-met; microtubule-associated proteins; eml4 gene
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