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      Is there a progression‐free survival benefit of first‐line crizotinib versus standard chemotherapy and second‐line crizotinib in ALK‐positive advanced lung adenocarcinoma? A retrospective study of Chinese patients

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          Abstract

          Although crizotinib has demonstrated promising efficacy and acceptable toxicity in patients with advanced non‐small cell lung cancer ( NSCLC), the available evidence in Chinese populations is currently limited. This study compared the progression‐free survival ( PFS) of Chinese patients with anaplastic lymphoma kinase ( ALK )‐positive, advanced lung adenocarcinoma who received first‐line crizotinib therapy with that of patients who received first‐line standard chemotherapy, and also the PFS benefit of first‐line versus second‐line crizotinib treatment. Data on 80 patients with ALK ‐positive, advanced lung adenocarcinoma who received crizotinib or standard chemotherapy as first‐line treatments between June 2013 and December 2014 were retrospectively collected; 26 of the patients received crizotinib as second‐line therapy after progressive disease ( PD) occurred on first‐line chemotherapy. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors ( RECIST), version 1.1. The median PFS was 13.3 months (95% CI: 6.5–20.0 months) in patients who received first‐line crizotinib as compared with 5.4 months (95% CI: 4.4–6.5 months) in patients who received first‐line standard chemotherapy (adjusted hazard ratio for progression or death with crizotinib, 0.20; 95% CI: 0.11–0.36; < 0.001). In patients who received second‐line crizotinib therapy, the median PFS was 9.9 months (95% CI: 6.4–13.4 months). The difference between first‐line and second‐line crizotinib treatment was not statistically significant (adjusted hazard ratio for progression, 0.56; 95% CI: 0.29–1.11; = 0.092). Thus, there was a significant PFS benefit of first‐line crizotinib versus first‐line standard chemotherapy in Chinese patients with ALK ‐positive lung adenocarcinoma. Additionally, crizotinib showed promising efficacy in patients who received it as second‐line therapy after PD had occurred on first‐line chemotherapy.

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          Most cited references 18

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          Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

          Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.
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            Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

            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. 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. 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. 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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              Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.

              In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
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                Author and article information

                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                16 February 2016
                June 2016
                : 5
                : 6 ( doiID: 10.1002/cam4.2016.5.issue-6 )
                : 1013-1021
                Affiliations
                [ 1 ] Department of Pulmonary MedicineShanghai Chest Hospital Shanghai Jiao Tong University ShanghaiChina
                Author notes
                [* ] Correspondence

                Liyan Jiang, Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241# HuaiHai (W.) Rd, Shanghai 200030, China. Tel: +86 13916146759; Fax: +86 021‐32260856; E‐mail: Jiang_liyan2000@ 123456126.com

                Article
                CAM4659
                10.1002/cam4.659
                4924358
                26880708
                © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 9
                Product
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                cam4659
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:28.06.2016

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