A Study of Camrelizumab Combined With Chemotherapy Sequential Camrelizumab Combined With Apatinib Treatment of Advanced NSCLC

Inclusion Criteria:

1. The subjects were 18-70 years old when they signed the informed consent form, and theage was unlimited for men and women;
2. The late stage (Ⅲ b/ Ⅲ C) and stage IV non-small cell lung cancer (according to AICCEighth Edition) which can not be removed by operation and can not be treated withradical radiotherapy and chemotherapy confirmed by histopathology or cytology;
3. EGFR mutation and alk translocation status were confirmed to be negative at any timeafter the initial diagnosis;
4. Subjects had not received systemic systemic chemotherapy for advanced / metastaticNSCLC. Chemotherapy and / or radiotherapy are allowed to be used as part of newadjuvant / adjuvant treatment, provided that the treatment has been completed for atleast six months before the diagnosis of advanced or metastatic diseases;
5. ECoG score; 0-1 point;
6. According to RECIST v1.1, subjects must have measurable target lesions through CT orMRI examination. The imaging assessment of tumor was performed within 28 days beforethe first drug use;
7. The main organs function normally, and the test results during screening must meet thefollowing requirements:

1. The blood routine examination standard should meet the requirements (no bloodtransfusion and blood products within 14 days, no correction by G-CSF and otherhematopoietic stimulating factors): A. Hemoglobin (HB) ≥ 90 g/l; B. Neutrophil number (ANC) ≥ 1.5 × 109/L； C. Platelet count (PLT) ≥ 100 × 109/L； 2) Biochemical examination shall meetthe following standards: A. TBIL was lower than 1.5 upper limit of normal value (ULN); B.ALT and AST were less than 2.5 ulin, but < 5 uld in liver metastasis; C. The serumcreatinine (CR) < 1.5 ULN or the clearance rate of endogenous creatinine was more than 60ml / min (Cockcroft Gault formula); D. The results of routine urine test showed that uro wasless than 2+ or 24 hours urinary protein was less than 1G; 8. Men and women of gestationalage must agree to take adequate contraceptive measures throughout the study period andwithin 6 months after the treatment. Sign written informed consent, and it is expected to be in good compliance with theresearch plan.

Exclusion Criteria:

1. Mixed NSCLC confirmed by histology or cytology, including mixed squamous cellcarcinoma and small cell lung cancer;
2. Previously received anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody,anti-CTLA-4 antibody (or any other antibody acting on T cell costimulation orcheckpoint pathway) or any VEGF / VEGFR inhibitor;
3. Patients with active brain metastases (for patients with stable symptoms of brainmetastases after treatment, they can be selected if they remain stable for at least 4weeks);
4. Imaging evidence of tumor cavity, tumor surrounding or invasion of large bloodvessels. In addition, the degree of proximity of the tumor to the large vessels shouldbe considered（ The major vessels in the chest include the main pulmonary artery, leftpulmonary artery, right pulmonary artery, four pulmonary veins, superior vena cava,inferior vena cava and aorta.
5. Immunosuppressive drugs were used within 28 days before the first use of karelizumab,excluding nasal and inhaled corticosteroids or physiological doses of systemicsteroids (i.e. not more than 10 mg / day prednisolone or other corticosteroids withthe same physiological dose of drugs);
6. Received systemic treatment of Chinese herbal medicine with anti-tumor indications orimmunomodulatory drugs (including thymosin, interferon and interleukin, except forlocal use for controlling pleural effusion) within 28 weeks before the firstadministration;
7. Inoculate live attenuated vaccine within 30 days of the first administration or withinthe expected period of the study（ For the new coronal vaccine vaccinators, whetherthey can be selected according to the judgment of the researchers)
8. According to the judgment of the researcher, there is uncontrolled pleural effusion,pericardial effusion or ascites, or the patient has received serous cavity effusiondrainage for treatment within 4 weeks before treatment.
9. Subjects with severe infection within 1 month before enrollment, including but notlimited to infection complications, bacteremia, severe pneumonia, etc; Subjects withany active infection, or fever of unknown origin > 38.5 ℃ occurred during screening orbefore the first administration;
10. Patients with active autoimmune disease or immunodeficiency, or with theabove-mentioned history, including but not limited to: autoimmune hepatitis,interstitial pneumonia, uveitis, rheumatoid arthritis, inflammatory bowel disease,hypophysitis, vasculitis, nephritis, etc.) were not included. The followingexceptions: Patients with a history of autoimmune hypothyroidism but receiving thyroidhormone replacement therapy were included in the study. After treatment with insulinregimen, patients with type 1 diabetes who have controlled glycemic control canparticipate in this study.
11. Subjects who received systemic therapy such as bronchodilators were not satisfied withasthma control and could not be included (those who had complete remission of asthmain childhood and did not need any intervention in adulthood could be included).
12. Human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS), untreated active hepatitis B, hepatitis C virus (hepatitis C antibodypositive, HCV-RNA higher than the lower limit of analysis method) or co infection ofhepatitis B and hepatitis C; Note: the hepatitis B subjects who met the followingcriteria also met the inclusion criteria: HBV viral load must be <1000 copy /ml (200IU/ml) before the first dose, and the subjects should be treated with anti HBV therapyduring the whole chemotherapy course to avoid virus reactivation. For the subjectswith anti HBC (+), HBsAg (-), anti HBS (-) and HBV viral load (-), preventive anti HBVtreatment is not necessary, but close monitoring of virus reactivation is needed;
13. Subjects have received or plan to receive solid organ or blood system transplantation (except corneal transplantation) during the study period;
14. Subjects with a history of other malignancies within five years (except for completetreatment of cervical cancer in situ or basal cell carcinoma or squamous cellcarcinoma or skin cancer);
15. He has hypertension and cannot be well controlled by antihypertensive drugs (systolicblood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg);
16. Clinical symptoms or diseases of heart that can not be well controlled, such as: (1)heart failure of NYHA grade 2 or above; (2) unstable angina pectoris; (3) myocardialinfarction within one year; (4) clinically significant supraventricular or ventriculararrhythmia requiring treatment or intervention; (5) QTc > 450ms (male); and; QTc > 470ms (female);
17. Coagulation dysfunction (INR > 2.0, Pt > 16S), bleeding tendency or receivingthrombolytic or anticoagulant therapy, low-dose aspirin and low molecular weightheparin are allowed for prophylactic use;
18. Clinically significant hemoptysis or hemoptysis more than half teaspoon (2.5ml) perday occurred within 2 months before admission; Or significant clinical bleedingsymptoms or clear bleeding tendency, such as gastrointestinal bleeding, hemorrhagicgastric ulcer, baseline fecal occult blood + + or above, or vasculitis, etc; Therewere deep and large ulcers, lesions closely related to big blood vessels and maxillaand mandible;
19. Arteriovenous thrombosis events occurred in the first 6 months, such ascerebrovascular accident (including transient ischemic attack, cerebral hemorrhage,cerebral infarction), deep venous thrombosis and pulmonary embolism, etc; Knownhereditary or acquired bleeding and thrombotic tendency (such as hemophilia,coagulation dysfunction, thrombocytopenia, etc.);
20. Routine urine examination showed that urine protein was ≥ +, and 24-hour urine proteinwas more than 1.0 G;
21. Currently participating in interventional clinical research treatment, or receivingother experimental drugs or research devices within 4 weeks before the firstadministration; Not fully recovered from toxicity and / or complications caused by anyintervention before the first administration (i.e., ≤ grade 1 or baseline, excludingfatigue or hair loss);
22. Have a clear history of allergy, and may have potential allergy or intolerance to thetest drug and its similar biological agents;
23. Those who have a history of psychotropic drug abuse and can not give up or have mentaldisorders; Other conditions that increase the risk associated with participating inthe study or trial drug and, according to the judgment of the investigator, may resultin patients not suitable for inclusion in the study