• To determine the mortality and major morbidity of stage IIIA (N2) and IIIB (T4 N2) NSCLC at thoracotomy of patients following 3 cycles of preoperative chemotherapy with paclitaxel, carboplatin and OSI-774 (Tarceva™). [ Time Frame: Following 3 cycles of treatment ] [ Designated as safety issue: No ]
  
• To evaluate extent of inhibition of EGFR phosphorylation by OSI-774 (Tarceva™) in tumor samples at the time of surgery. [ Time Frame: Tissue obtained for assessment at time of surgery ] [ Designated as safety issue: No ]
  

• To determine the pathologic complete response rate in stage IIIA (N2) and IIIB (T4 N2) NSCLC patients following 3 cycles of preoperative chemotherapy with paclitaxel, carboplatin and OSI-774. [ Time Frame: At time of surgery ] [ Designated as safety issue: No ]
  
• To evaluate the role of selected molecular markers as predictors of response. [ Time Frame: Tissue for molecular studies will be obtained pretreatment either at the time of diagnostic biopsy or mediastinoscopy ] [ Designated as safety issue: No ]
  
• To assess modulation of selected downstream signal transduction elements. [ Time Frame: Tissue for molecular studies will be obtained pretreatment either at the time of diagnostic biopsy or mediastinoscopy ] [ Designated as safety issue: No ]
  

This is a phase II, single institution open label randomized trial of induction carboplatin and paclitaxel plus/minus daily oral OSI-774 in patients with potentially resectable NSCLC that is stage IIIA and IIIB (T4 satellite nodules or invasion into T4 structures but no malignant effusion.) N3 disease is excluded. Patients will be required to have pathologically demonstrated N2 disease via mediastinoscopy. Forty patients will be treated with 3 courses of chemotherapy followed by surgery. Ten of these patients will be randomized to chemotherapy alone and 30 patients to chemotherapy plus OSI-774. The 10 patients will serve as a chemotherapy alone control for molecular endpoint analysis. OSI-774 will be stopped the night before surgery. At the time of surgery, pathologic response will be determined. Following surgery, patients will be treated with consolidation radiation therapy if there are positive margins or N2 lymph nodes at the time of resection. Patients who have no N2 disease at surgery will have the option of consolidation radiation therapy but will not be required to have it done. Patients not able to tolerate radiation even if they have N2 disease or positive margins at surgery may continue on this study. This will be followed by maintenance OSI-774 for patients from both arms of the study. OSI-774 will be continued as maintenance to a maximum of 2 years following surgery. Tissue for molecular studies will be obtained pretreatment either at the time of diagnostic biopsy or mediastinoscopy. Post-treatment tissue will be obtained at the time of surgery. This tissue will be assayed for defined molecular endpoints using immunohistochemistry, immunoprecipitation and mRNA expression analysis. Blood, urine, hair follicles, and skin samples will also be collected from patients who consent to provide these.

• Must have signed consent for LAB03-0383
• Pathologic documentation of NSCLC
• Stage IIIA and IIIB (T4 satellite nodules or invasion into T4 structures but no malignant effusion) with all patients requiring mediastinoscopy positive N2, potentially resectable disease. N3 disease is excluded.
• Measurable disease
• Zubrod performance status of 0 or 1
• Calculated post-resectional FEV1 of > 40%
• No prior chemotherapy or radiation for NSCLC
• No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient has been disease-free for at least five years. If patient is suspected or known to have basal or squamous cell skin cancer, this may be treated after induction chemotherapy is completed at the time of thoracotomy.
• WBC>4000/ul, ANC>1500/ul, platelets > 100,000/ul
• Serum creatinine < 1.5 ULN or calculated creatinine > 50 cc/min
• Total serum bilirubin <1.5 x ULN and SGPT or SGOT < 2 X ULN
• No post-obstructive pneumonia or other serious infection or other serious underlying medical condition that would impair ability of patient to receive protocol treatment, including prior allergic reactions to drugs containing cremophor.
• Pregnant or nursing women may not participate