Metformin in Stage IV Lung Adenocarcinoma

Inclusion Criteria:

1. Histologically or cytologically confirmed lung adenocarcinoma.
2. Stage IV disease as defined by AJCC 7th edition staging.
3. At least one measurable lesion (as defined by RECIST v1.1).
4. No prior radiotherapy, chemotherapy, surgery, target therapy, or immunotherapy for NSCLC. (Except the surgery for biopsy or port-A implantation, palliative localized radiotherapy for bone metastasis).
5. Age ≤ 80 years old and ≥ 20 years old.
6. ECOG performance status of 0-2.
7. Adequate organ function, including followings

   Bone marrow:

   Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L; WBC ≥ 3.0 x 10\^9/L Platelet count ≥ 100 x 10\^9/L Hemoglobin ≥ 9g/dL

   Hepatic:

   Total bilirubin level ≤ 1.0 x UNL AST and ALT ≤ 3.0 x UNL;

   Renal:

   Creatinine level ≤ 1.5 mg/dL in men, ≤1.4 mg/dL in women; or Estimated CCr ≥ 60 mL/min. (CCr is estimated by Cockcroft-Gault formula, as appendix II)(CCr is estimated by Cockcroft-Gault formula)
8. Estimated life expectancy of at least 6 months.
9. Written (signed) Informed Consent.

Exclusion Criteria:

1. With other primary malignancies, except those remain disease-free for 3 or more years after curative treatment, basal cell cancer of the skin or in situ cervical cancer.
2. Use of other anti-cancer therapy, including chemotherapy, target therapy, immunotherapy, radiotherapy, and hormone therapy.
3. Prior participation in any investigational drug study within 28 days.
4. Use of anti-IL-6 or IL-6-lowering agents.
5. Use of metformin in the past 6 months.
6. Poor controlled diabetes (HbA1c ≥ 8.0%).
7. Known hypersensitivity or intolerance to metformin.
8. Congestive heart failure with NYHA functional class II\~IV.
9. History of lactic acidosis.
10. Significant concurrent medical diseases, such as unstable angina, acute or recent myocardial infarction (\< 6 months before enrollment), COPD with frequent exacerbation, uncontrolled hypertension, or recent CVA (\< 6 months before enrollment).
11. Active uncontrolled infections or HIV infection.
12. Psychiatric disorders that would compromise the patient's compliance or decision.
13. Current or planned pregnancy, or breast feeding in women.
14. Poor compliance.