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 for multidisciplinary therapy), metastatic (IV), or recurrent patients with squamous cell non-small cell lung cancer, and with a resistant EGFR - TKI treatment; Did not receive the systemic chemotherapy previously; Do not accept that diagnosis based on sputum cytology alone; If mixed with a variety of tumors, the main cell types should be classified;
• 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 For patients without liver metastasis, aspartate aminotransferase (AST) and alanine aminotransferase (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 calculation value greater than 50 ml/min, and Forced the urine dipstick test results showed that urinary protein < 2 +. For those with baseline urine dipstick test showed that urinary protein of > 2 +, a 24-hour urine collection and 24 hours urine protein content must be 1 gb or less may be selected;

• Within 7 days before study treatment, international standardization ratio (INR) 1.5 or less, 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 with squamous cell as the main component;
• Had a history of hemoptysis, which produce at least 1/2 teaspoon of blood within 3 months 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 should conduct cranial CT or MRI scans;
• Received radical chest radiotherapy within 28 days before selected; Received palliative extra-chest bone radiotherapy 2 weeks before the first dose of study;
• Received the large operation (including open chest biopsy), a major trauma, or anticipated the need for major surgery during the research and treatment within 28 days before the selection;
• A small surgery operations (including catheter) performed 48 hours before the first bevacizumab injection;
• Use of aspirin (> 325 mg/day) or other known to inhibit platelet function of non-steroidal anti-inflammatory drugs (NSAIDs) within 10 days before treatment;
• Using a full dose of oral or parenteral anticoagulants or thrombolytic agent for treatment; Allow the preventive use of anticoagulants;
• History and examination results show that with inherited bleeding tendency or blood coagulation disorders, which may increase the risk of hemorrhage patients;
• Uncontrolled hypertension, systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg);
• Hypertensive crisis or encephalopathy patients of hypertension;
• Cardiovascular disease with clinical significance (such as active), including but not limited to transient ischemic attack (< 6 months before selected), myocardial infarction (< 6 months before selected), unstable angina, the classification of the New York heart association class II or higher congestive heart failure, needing drug treatment during the study period, which may interfere with the treatment, serious arrhythmia that drugs cannot control;
• In the recent six months of significant vascular disease (including but not limited to aortic 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-abdominal abscess < 6 months before selected.
• During the study period and six months after bevacizumab, women with uterus (except postmenopausal status in the past 24 months), but without the use of effective contraceptive methods; During the study period and 90 days after bevacizumab, men do not 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 or participated in another clinical trial;
• Known for bevacizumab or any of its accessories and any chemotherapy drug ingredients allergy;
• Needing intravenous antibiotics for continuing or active signs of infection. Other disease, neurological or metabolic dysfunction; Physical findings or laboratory test results indicate the contraindication to use drugs or high-risk of the complications during the treatments.
• Diagnosed with trachea-esophageal fistula;
• Had other malignancies other than NSCLC in the last 5 years, except those with adequate treatment of cervical carcinoma in situ, basal cell or squamous cell skin cancer, radical surgery of localized prostate cancer, radical surgery of ductal carcinoma in situ;
• The history and examination results show with thrombotic disease < 6 months before selected.