A prospective double-blind randomized Phase III study of 300 mg vs. 150 mg erlotinib in current smokers with locally advanced or metastatic NSCLC in second-line setting after failure on chemotherapy

Disease Specific Inclusion Criteria:;1. Histologically or cytologically documented inoperable, locally advanced (stage IIIB with supraclavicular lymph node metastases or malignant pleural or pericardial effusion) or metastatic (stage IV) NSCLC disease.;2. Measurable disease must be characterized according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Eisenhauer et al., 2009).;3. Must have received one prior platinum-based chemotherapy regimen for advanced NSCLC and now exhibit PD, and must have recovered from any treatment-related toxicity.;4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.;5. Life expectancy * 12 weeks.;6. Current cigarette smoker (having smoked > 100 cigarettes in entire lifetime and currently smoking on average * 1 cigarette per day), not intending to stop smoking during the study.;7. Adequate hematological function:;* Absolute neutrophil count (ANC) * 1.5 x 109/L, and;* Platelet count * 100 x 109/L, and;* Hemoglobin * 9 g/dL (may be transfused to maintain or exceed this level).;8. Adequate liver function:;* Total bilirubin < 1.5 x upper limit of normal (ULN), and;* AST, ALT < 2.5 x ULN in patients without liver metastases; < 5 x ULN in patients with liver metastases.;9. Adequate renal function:;* Serum creatinine * 1.25 x ULN,;* Creatinine clearance * 60 ml/min.;10.Female patients must be either: a) postmenopausal (24 months of amenorrhea), b) surgically sterile or c) not pregnant (negative urine or serum pregnancy test within 3 days of randomization).;Male patients must be surgically sterile or agree to use a barrier method of contraception.;Female and male patients must be willing to use an effective method of contraception during the trial and for 60 days after last administration of erlotinib. cceptable methods of contraception include an established hormonal therapy or intrauterine device for females, or the use of a barrier contraceptive (i.e. diaphragm or condoms) with spermicide.;General Inclusion Criteria:;11.Patients able and willing to give written informed consent. The consent must be obtained before the first screening procedure.;12.Males or females aged * 18 years.;13.Able to comply with the required protocol and follow-up procedures, and able to receive oral medications.;14.Patients able to read, and understand the local language(s) for which the Functional Assessment of Cancer Therapy * Lung (FACT-L) questionnaires are available.

Cancer Treatment Related Exclusion Criteria:;1. Received prior therapy against EGFR, either with antibody or small molecule (tyrosine kinase inhibitor).;2. Received radiotherapy within 28 days prior to enrolment.;3. Received treatment with any other investigational agent, or participated in another clinical trial, with the following exceptions:;* Chemotherapy-only trials are permitted including where chemotherapy in combination with bevacizumab has been used (if study drug completed * 28 days prior to receiving the first dose of erlotinib).;* Previous adjuvant or neo-adjuvant treatment for non-metastatic disease is permitted if completed * 6 months before receiving the first dose of study drug. ;* Prior surgery is permitted if performed * 4 weeks before receiving the first dose of study drug and the patient is fully recovered.;* Prior localized radiotherapy is permitted if it was not administered to target lesions selected for this study, unless progression of the selected target lesions within the radiation portal is documented, and provided it has been completed * 4 weeks before receiving the first dose of study drug.;* Participation in a methodological or observational study in which no investigational agent was given.;4. Received more than one line of chemotherapy (first-line maintenance chemotherapy after first-line platinum-based chemotherapy is allowed) for locally advanced/metastatic NSCLC.;Cancer Related Exclusion Criteria:;5. History of breast cancer or melanoma at any time, or history of another malignancy in the last 5 years with the exception of the following:;* Other malignancies cured by surgery alone and having a continuous disease-free;interval of * 5 years.;* Cured basal cell carcinoma of the skin and cured in situ carcinoma of the uterine cervix.;6. History and symptomatic evidence of brain metastases.;Other Study Drug Related Exclusion Criteria;7. Known hypersensitivity to erlotinib or any of its excipients.;8. Any significant ophthalmologic abnormality, especially severe dry eye syndrome, keratoconjunctivitis sicca, Sjögren syndrome, severe exposure keratitis or any other disorder likely to increase the risk of corneal epithelial lesions. The use of contact lenses is not recommended during the study. The decision to continue to wear contact lenses should be discussed with the patient*s treating oncologist and the;ophthalmologist.;9. Coumarins (CoumadinTM; warfarin) use. If the patient requires anti-coagulation therapy, then the use of low molecular weight heparin instead of coumarins is recommended where clinically possible.;General Exclusion Criteria;10.Unstable systemic disease (including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, myocardial infarction within the previous year, serious cardiac arrhythmia requiring medication, hepatic, renal, or metabolic disease).;11.Evidence of any other disease, neurological or metabolic dysfunction, physical examination or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.;12.Female patients of childbearing potential who are: a) pregnant according to urine or serum pregnancy test within 3 days of randomization, b) breast-feeding. Female and male patients of reproductive potential not willing to use an effective method of;contraception during the trial and for 60 days after last administration of erlotinib.;13.Patients with pre-existing parenchymal lung disease such as pulmonary fibrosis, lymphangiosis carcinomatosis.;14.Patients with known infection with HIV, HBV, HCV. Testing is not required in the absence of clinical signs and symptoms suggestive of these conditions.;15.Patients assessed by the investigator to be unable or unwilling to comply with the;requirements of the protocol.