This trial will evaluate whether the sequential administration of Cisplatin/Vinorelbine/Bevacizumab followed by Docetaxel/Gemcitabine/Bevacizumab versus the Cisplatin/Docetaxel/Bevacizumab combination as first line treatment offers a survival advantage in patients with locally advanced or metastatic NSCLC.

An unanswered question in first line treatment of non small cell lung cancer (NSCLC) is whether the administration of more than 2 active drugs provides greater efficacy than a two-drug combination. Docetaxel/gemcitabine combination is a well tolerated regimen, which has comparable efficacy to docetaxel/cisplatin or vinorelbine/cisplatin. In a recent phase II study in first line treatment of advanced or metastatic NSCLC, the sequential administration of vinorelbine/cisplatin followed by docetaxel/gemcitabine produced a response rate of 45.8% and a 1-year survival rate of 51%. The addition of bevacizumab to a platinum-based regimen provided a survival benefit in patients with advanced or metastatic NSCLC.

Inclusion Criteria:

• Histologically confirmed, unresectable locally advanced (stage IIIB with pleural effusion) or metastatic (stage IV) non-squamous NSCLC

• Performance status (WHO) 0-1

• Adequate bone marrow (ANC ≥ 1,500/mm3, PLT ≥ 100,000/mm3, Hgb ≥ 11 g/dL), liver (Bilirubin ≤ 1.5 UNL, SGOT/SGPT ≤ 2.5 UNL, ALP ≤ 5 UNL), and renal function (Creatinine ≤ UNL - if borderline, creatinine clearance should be ≥ 60 mL/min)

• No previous chemotherapy or immunotherapy for advanced/metastatic NSCLC is allowed

  --Previous radiotherapy is allowed provided that the measurable lesions are outside the radiation fields

• Measurable disease, defined as at least 1 bidimensionally measurable lesion ≥ 20 X 10 mm

• Patient able to take oral medication

• Absence of active CNS disease

• Paraffin embedded sample of primary or metastatic tumor diagnostic specimen must be available

• Patients must be able to understand the nature of this study and give written informed consent

Exclusion Criteria:

• Pregnant or lactating women
• Women of child-bearing age unable or unwilling to take effective contraceptive measures
• Active CNS disease, brain metastases, or leptomeningeal involvement
• Symptomatic neuropathy > grade1 according to the NCI CTCAE (version 3.0)
• Cardiovascular disease (class II-IV NYHA congestive heart failure, myocardial infarction within the previous 4 months, LVEF < normal, uncontrolled hypertension, ventricular arrhythmia), anticoagulation treatment or thrombotic event within the previous 6 months
• Active infection, requiring IV antibiotic treatment, within the previous 2 weeks
• Long-term oxygen therapy
• Second primary malignancy, except for non-melanoma skin cancer and in situ cervical cancer
• Radiotherapy within the previous 4 weeks
• Previous radiotherapy to the only measurable lesion
• Concurrent treatment with other anti-cancer drug
• Uncontrolled hypercalcemia
• Known allergy to drugs with similar chemical structure to study drugs. Concurrent corticosteroids, except for chronic therapy with methylprednisolone ≤ 20 mgr daily (or equivalent) for more than one month