Trial Comparing Cetuximab With Pemetrexed/Cetuximab Therapy for Non-Small Cell Lung Cancer

Inclusion Criteria:

* Diagnosis of locally advanced or metastatic (Stage III or IV at entry) non-small cell lung cancer (NSCLC) that is not amenable to curative therapy.
* ECOG performance status 0-2
* Patients must have been previously treated with one platinum-containing or taxane-containing chemotherapy regimen for locally advanced or metastatic disease. Patients are also eligible if they have received one platinum-based chemotherapy regimen as neoadjuvant or adjuvant chemotherapy, but must have received an additional chemotherapy regimen upon recurrence.
* No more than two prior systemic anti-cancer therapies will be allowed.
* Prior radiation therapy is allowed to \<25% of the bone marrow. Prior radiation to the whole pelvis is not allowed, Prior radiotherapy must be completed at least 2 weeks before study enrollment, and the patient must have recovered from the acute toxic effects of the treatment prior to study enrollment.
* Patients must have signed an approved informed consent.
* Male and female patients with reproductive potential must use an approved contraceptive method if appropriate (eg, intrauterine device, birth control pills, or barrier device) during and for 3 months after the study. Female patients must either not be of child bearing potential or have a negative pregnancy test within 7 days of treatment. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
* Age\>18
* Measurable disease in accord with RECIST criteria
* Bone marrow Function: absolute neutrophil count (ANC)\>/=1,500/ul, platelets \>/=l00,000, hemoglobin\> 9g/dL
* Renal function: creatinine clearance (calculated by Cockcroft and Gault method) \>/= 45mL/min
* Hepatic function: bilirubin \</=1.5 x ULN; ALT/AST ,/= 2.5 x ULN; Albumin \>/=2.5 g/dL

Exclusion Criteria:

* Prior treatment with pemetrexed
* Prior therapy that targets the EGF pathway.
* Active or uncontrolled infection.
* Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, and congestive heart failure.
* Pleural or pericardial effusions that cannot be completely evacuated prior to pemetrexed therapy.
* Acute hepatitis or known HIV.
* Prior severe infusion reaction to a monoclonal antibody.
* Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s).
* Pregnancy or Breast-feeding.
* Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
* Inability to interrupt aspirin, or other nonsteroidal anti-inflammatory agents for a 5-day period.
* Inability or unwillingness to take folic acid or vitamin B12 supplementation.