A Phase II Selection Design of Pharmacodynamic Separation of Carboplatin/Paclitaxel/OSI-774 (Erlotinib; NSC-718781) or OSI-774 Alone in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients with Performance Status 2 (PS-2) Selected by Serum Proteomics

Newly diagnosed selected Stage IIIB (T4 lesion due to malignant pleural effusion) or Stage IV, advanced primary NSCLC (adenocarcinoma, large cell carcinoma, squamous cell carcinoma or unspecified) or recurrent disease after previous surgery and/or irradiation. Must show evidence of EGFR TKI therapy benefit (i.e. qualify as "VeriStrat Positive") as determined by central analysis. Must have measurable or non-measurable disease (see Section 10.1) documented by CT, MRI, X-ray, physical exam or nuclear exam. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Measurable disease must be assessed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration. Must not have symptomatic brain metastases. Patients with untreated brain metastases are ineligible. All patients with neurologic abnormalities on physical examination or symptoms must have a negative pretreatment CT or MRI scan of the brain days prior to registration. Patients with treated brain metastases are eligible if: metastases have remained controlled for at least two weeks following treatment, AND patient has no residual neurological dysfunction off corticosteroids. Zubrod Performance Status of 2. May have received prior radiation therapy provided that at least 14 days have elapsed since the completion of prior radiation therapy and patients have recovered from all associated toxicities at the time of registration. May have received prior surgery provided that at least 21 days have elapsed since surgery (thoracic or other major surgeries) and patients have recovered from all associated toxicities at the time of registration. Must be no anticipation of need for major surgical procedures during protocol treatment. May have received adjuvant chemotherapy, but at least one year must have elapsed since completion of this type of therapy. Must not have received prior systemic hormonal therapy, chemotherapy or biologic therapy for advanced non-small cell lung cancer. must not have received prior therapy with EGFR inhibitors. Must have a serum creatinine </= 2 x IULN or a measured or calculated creatinine clearance >/= 50 mL/min. These tests (or the serum creatinine value used to calculate the creatinine clearance) must be obtained within 28 days prior to registration. Must not have gastrointestinal tract disease resulting in an inability to take enteral medication, malabsorption syndrome, a requirement for IV alimentation, had prior surgical procedures affecting absorption or uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis). Must be offered participation in the additional embedded translational medicine studies as outlined in Section 15.2. With the patient's consent, blood, plasma and tissue will be submitted for testing. Must not have a significant history of cardiac disease, i.e., uncontrolled high blood pressure, unstable angina, congestive-heart failure, myocardial infarction within the last six months, or cardiac ventricular arrhythmias requiring medication. Must be willing to provide prior smoking history. No prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years. Must not be pregnant or nursing.