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ERLOTINIB AS A SINGLE AGENT IN PATIENTS p WITH ADVANCED OR METASTATIC NSCLC: A MULTIVARIATE ANALYSIS IN A PROSPECTIVE ST

Introduction . Lung cancer is the leading cause of cancer death and despite considerable medical advances, the five years survival is about 14%. 1Erlotinib is a tyrosine kinase inhibitor of the human epidermal growth factor receptor (HER1/EGFR) that provides a targeted mechanism of action through t

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ERLOTINIB AS A SINGLE AGENT IN PATIENTS p WITH ADVANCED OR METASTATIC NSCLC: A MULTIVARIATE ANALYSIS IN A PROSPECTIVE ST

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    1. ERLOTINIB AS A SINGLE AGENT IN PATIENTS (p) WITH ADVANCED OR METASTATIC NSCLC: A MULTIVARIATE ANALYSIS IN A PROSPECTIVE STUDY

    2. Introduction Lung cancer is the leading cause of cancer death and despite considerable medical advances, the five years survival is about 14%. 1 Erlotinib is a tyrosine kinase inhibitor of the human epidermal growth factor receptor (HER1/EGFR) that provides a targeted mechanism of action through the inhibition of receptor phosphorylation and subsequent intracellular signal transduction cascade, DNA synthesis and cell growth.2-5 Erlotinib is approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen on the basis of the results of a large double-blind, placebo-controlled trial (BR.21).6 The TargeT trial was a Spanish non-randomized phase II trial evaluating the efficacy and safety of erlotinib in patients with either advanced or metastatic NSCLC. 1. Jemal, C. et al. CA Cancer J Clin. 2006 Mar-Apr;56(2): 106-30. 2. Arteaga, C. Semin Oncol. 2003;30: 3-14.3. Voldborg, BR. et al. Ann Oncol. 1997;8: 1197-1206.4. Scagliotti, GV. et al. Clin Cancer Res. 2004;10: 4227-4232.5. Hirsch, FR, et al. J Clin Oncol. 2003;21: 3798-3807.6. Shepherd, FA. et al. N Engl J Med. 2005; 353: 123-132.

    3. Study Design (I) Patients Patients with histologically confirmed stage IIIB or IV NSCLC who had received treatment with chemotherapy in first or second line were eligible for recruitment into the TargeT trial. Chemotherapy-naive patients non suitable for first line conventional chemotherapy were also eligible for the study. Eligibility criteria were: >18 years old, ECOG 0-2, adequate bone marrow, hepatic, and renal function and written informed consent. Trial design Open-label, multicenter, non-randomized, phase II trial. Patients were treated with erlotinib 150 mg/day until disease progression or withdrawal.

    4. Study Design (II) Efficacy assessments Physical Examination. Radiological assessment of tumor response by CT Scan was performed every six weeks. Responses were evaluated according to RECIST criteria and confirmed 6 weeks later. Safety assessments Evaluation of the safety profile of erlotinib as determined by NCI CTCAE version 3.0.

    5. Objectives Primary Endpoint Evaluate time to progression (TTP) in the intent to treat (ITT) population with erlotinib administered as first, second and third or successive lines of treatment. Secondary Endpoints Determine the efficacy of erlotinib in terms of clinical benefit (CR, PR and SD) when administered to patients with advanced or metastatic NSCLC. Determine overall survival in this patient population. Define safety profile of erlotinib as determined by NCI-CTCAE v3.0.

    6. Results (I) From June 2004 to August 2005, a total of 975 patients were enrolled in the study. 565 patients had measurable disease and were evaluable for response: 4 CR, 85 PR, 239 SD and 237 PD.

    7. Results (II): Baseline Characteristics

    8. Results (III): Univariate Analysis of Response

    9. Results (IV): TTP among All Evaluable Patients

    10. Results (V): TTP by Smoking History

    11. Results (VI): TTP by Histology

    12. Results (VII): TTP by Line of Treatment

    13. Results (VIII): OS among All Patients

    14. Results (IX): OS by Smoking History

    15. Results (X): OS by Histology

    16. Results (XI): OS by Line of Treatment

    17. Results (XII): Safety Most common adverse events related to erlotinib were rash and diarrhea. No unexpected toxicities were observed. Rash was the predominant toxicity, occurring in 61.5% of patients. Most cases of rash were mild to moderate. There were only 10 cases of grade 4 rash (1.2%). Diarrhea was observed in 30.2% of patients (0.6% grade 4).

    18. Conclusions This large experience confirms erlotinib as an active agent in patients with advanced NSCLC, achieving disease control rate >50%, median TTP 3.5 months and median survival time of 5.7 months. The effect in disease control rate seems not to be dependent on performance status. Use of erlotinib in first line of treatment in patients not suitable for cytotoxic chemotherapy achieves better results than in 2nd and 3rd or successive lines of treatment in terms of TTP. The results of erlotinib as treatment of 2nd and 3rd line do not differ. No significant differences in TTP or survival were found between adenocarcinoma and SCC in the present study. In multivariate analysis, the absence of smoking history is the most significant predictive factor for a longer TTP.

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