Erlotinib Therapy and Subsequent Development of Mechanisms of Secondary Resistance in Patients With NSCLC

Inclusion Criteria: * Histologically or cytologically confirmed non-small cell lung cancer, stage IV or IIIB with a malignant pleural or pericardial effusion. Patients with stage I or II non-small cell lung cancer who have undergone surgical resection but who subsequently relapse with metastatic disease or a malignant pleural effusion are also eligible. * Documentation of a sensitizing mutation of the epidermal growth factor receptor. In addition, there must be a sufficient tissue for analysis of KRAS (the oncogene from the Kirsten rat sarcoma virus) mutations and MET amplification. * At least one measurable or evaluable site of disease as defined by revised RECIST (version 1.1) criteria. * 18 years of age or older * No more than one prior systemic therapy regimen for advanced non-small cell lung cancer. Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC will not count towards this total as long as it was completed at least 6 months prior to enrollment and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than 6 months prior to the time of screening will count as a prior regimen. * 3 or more weeks since prior major surgery * 2 or more weeks since prior radiation * ECOG performance status 0-1 * Life expectancy \> 8 weeks * Adequate hematologic, renal, and hepatic function * Willingness to undergo repeat tumor biopsy at the time of disease progression. Exclusion Criteria: * Untreated and/or uncontrolled central nervous system metastases. Patients with prior brain metastases must have had definitive treatment (radiation or surgery) and must be clinically stable off steroids for at least 1 week prior to enrollment. * More than one prior systemic chemotherapy for advanced non-small cell lung cancer. , Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC willnot count towards this total as long as it was completed at least 6 months prior to enrollment and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than 6 months prior to the time of screening will count as a prior regimen. * Prior exposure to erlotinib or other treatments targeting the HER family axis. * Active malignancies within the past 3 years, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin. * Any process that compromises the ability to swallow and/or absorb oral medication. * Incomplete healing from previous surgery * A history of any of the following autoimmune skin disorders: Sjogren's syndrome, scleroderma, dermatomyositis, and systemic lupus erythematosus. * Significant medical history or unstable medical conditions. * Concurrent use of warfarin. Patients must be off warfarin for at least one week prior to initiation of erlotinib. Other non-warfarin anticoagulants are permitted. * Patients who require ongoing concomitant use of one of the strong inhibitors/inducers of CYP3A4. * Pregnant or breastfeeding. Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation.