Efficacy and Safety Study of Bevacizumab Plus Chemotherapy in EGFR-TKI Resistant Non-Squamous Non-Small Cell Lung Cancer

Inclusion Criteria:

• Histology and cytology confirmed locally advanced (Ⅲb, not suitable formultidisciplinary therapy), metastatic (IV), or recurrent patients with squamous cellnon-small cell lung cancer, and with a resistant EGFR - TKI treatment; Did not receivethe systemic chemotherapy previously; Do not accept that diagnosis based on sputumcytology alone; If mixed with a variety of tumors, the main cell types should beclassified;

• The age range from 18 to 75-year-old;

• The physical status score (ECOG PS) 0 and 1;

• The expected survival time greater than 12 weeks;

• Enough hematology function: Absolute neutrophils value (ANC) acuity 1.5 x 109 / L, and Platelet count, 100 x 100 / L,or and Hemoglobin 9 g/dL or higher (can maintain blood transfusion or beyond this level) -Enough liver function: Total bilirubin < 1.5 x upper limit of normal (ULN), and Forpatients without liver metastasis, aspartate aminotransferase (AST) and alanineaminotransferase (ALT) < 2.5 x ULN; For patients with liver metastases in, both < 5 x ULN.

• Enough renal function: Serum creatinine < 1.5 x ULN or creatinine clearance calculationvalue greater than 50 ml/min, and Forced the urine dipstick test results showed thaturinary protein < 2 +. For those with baseline urine dipstick test showed that urinaryprotein of > 2 +, a 24-hour urine collection and 24 hours urine protein content must be 1gb or less may be selected;

• Within 7 days before study treatment, international standardization ratio (INR) 1.5 orless, and part of promoting the prothrombin time (PTT or aPTT) 1.5 x ULN or less;

• To research and follow-up compliance program;

• The participants understand and voluntarily signed written informed consent.

Exclusion criteria: Meet the following any exclusion criteria cannot enter the trial;

• Mixed non-small cell and small cell carcinoma, or mixed adeno-squamous cancer withsquamous cell as the main component;

• Had a history of hemoptysis, which produce at least 1/2 teaspoon of blood within 3months before the selection;

• The image shows signs of tumor invasion of large blood vessels.

• Metastases to central nervous system; Within 28 days before the deal patients shouldconduct cranial CT or MRI scans;

• Received radical chest radiotherapy within 28 days before selected; Receivedpalliative extra-chest bone radiotherapy 2 weeks before the first dose of study;

• Received the large operation (including open chest biopsy), a major trauma, oranticipated the need for major surgery during the research and treatment within 28days before the selection;

• A small surgery operations (including catheter) performed 48 hours before the firstbevacizumab injection;

• Use of aspirin (> 325 mg/day) or other known to inhibit platelet function ofnon-steroidal anti-inflammatory drugs (NSAIDs) within 10 days before treatment;

• Using a full dose of oral or parenteral anticoagulants or thrombolytic agent fortreatment; Allow the preventive use of anticoagulants;

• History and examination results show that with inherited bleeding tendency or bloodcoagulation disorders, which may increase the risk of hemorrhage patients;

• Uncontrolled hypertension, systolic blood pressure > 150 mmHg and/or diastolic bloodpressure > 100 mmHg);

• Hypertensive crisis or encephalopathy patients of hypertension;

• Cardiovascular disease with clinical significance (such as active), including but notlimited to transient ischemic attack (< 6 months before selected), myocardialinfarction (< 6 months before selected), unstable angina, the classification of theNew York heart association class II or higher congestive heart failure, needing drugtreatment during the study period, which may interfere with the treatment, seriousarrhythmia that drugs cannot control;

• In the recent six months of significant vascular disease (including but not limited toaortic aneurysm or recent arterial thrombosis that need surgical repair);

• Non healing wounds, active stage of peptic ulcer or bone fracture.

• A abdominal fistula, gastrointestinal perforation or history of intra-abdominalabscess < 6 months before selected.

• During the study period and six months after bevacizumab, women with uterus (exceptpostmenopausal status in the past 24 months), but without the use of effectivecontraceptive methods; During the study period and 90 days after bevacizumab, men donot agree to use effective methods of contraceptive methods;

• Pregnant women and nursing mothers;

• In included in the first 28 days, have received any other test drug treatment orparticipated in another clinical trial;

• Known for bevacizumab or any of its accessories and any chemotherapy drug ingredientsallergy;

• Needing intravenous antibiotics for continuing or active signs of infection. Otherdisease, neurological or metabolic dysfunction; Physical findings or laboratory testresults indicate the contraindication to use drugs or high-risk of the complicationsduring the treatments.

• Diagnosed with trachea-esophageal fistula;

• Had other malignancies other than NSCLC in the last 5 years, except those withadequate treatment of cervical carcinoma in situ, basal cell or squamous cell skincancer, radical surgery of localized prostate cancer, radical surgery of ductalcarcinoma in situ;

• The history and examination results show with thrombotic disease < 6 months beforeselected.