Pemetrexed was known to be effective to pulmonary adenocarcinoma and gefitinib was known to be more effective to non-small cell lung cancer (NSCLC) patients with clinical characteristics such as adenocarcinoma, never smoker and female.

The investigators try to evaluate which drug (pemetrexed vs gefitinib) is more efficious to NSCLC patients with clinical characteristics such as adenocarcinoma and never smoking history as second- or further-line therapy.

Inclusion Criteria:

1. Histologically confirmed pulmonary adenocarcinoma including bronchioloalveolar, but except adenosquamous cell carcinoma
2. Stage IIIB (malignant pleural effusion and/or pleural seeding), stage IV and relapsed non-small cell lung cancer
3. Failed with 1st line platinum-based chemotherapy or relapsed within 12 months after adjuvant platinum-based chemotherapy)
4. Never smoker (less than 100 cigarette for the life time)
5. 18 year or older
6. ECOG 0-2
7. No history of biologic or immunotherapy
8. Tolerable renal function ( creatine clearance rate is 60ml/min or more)
9. Tolerable hepatic function (Serum bilirubin ≤ 1.25 x UNL, AST (SGOT) and ALT (SGPT) ≤ 2.5 x UNL, alkaline phosphatase ≤5 x UNL)

Exclusion Criteria:

1. symptomatic brain metastasis
2. previously treated with EGFR tyrosine kinase inhibitor
3. previously treated with antifolate agents
4. poor oral absorption
5. patients with active infection
6. uncontrolled diabetes mellitus
7. significant cardiovascular disease (uncontrolled hypertension, history of myocardial infarction or unstable angina within 6 months, congestive heart failure)
8. pregnant or nursing patients
9. history of malignant disease within 3 years before the enrollment except for cured non-melanomatous skin cancer, cervical carcinoma in situ, or thyroid carcinoma