Efficacy and Safety of Maintenance Apatinib Combined With Pemetrexed in Advanced Non-squamous Non-small Cell Lung Cancer Patients

Inclusion Criteria:

1. Histologically or cytologic confirmed，locally advanced and/or metastatic non-squamous NSCLC of stage IIIB or IV or recurrent NSCLC
2. At least one measurable lesion
3. If genetic testing (EGFR/ALK) is a sensitive EGFR mutation or ALK fusion gene positive, required for first line progress after targeted therapy;Without mutations, required for first-line treatment;
4. Pemetrexed combined platinum did not progress by RECIST curative effect evaluation after 4 cycles of chemotherapy
5. ≥ 18 years of age ,Male or female
6. Eastern Cooperative Oncology Group(ECOG)performance scale 0 - 2.
7. Life expectancy of more than 3 weeks.
8. Adequate hepatic, renal, heart, and hematologic functions (Absolute Neutrophil Count(ANC) ≥ 1.5×109/L, Platelet (PLT) ≥ 100×109/L, Hemoglobin(HB) ≥ 100 g/L, total bilirubin within 1.5×the upper limit of normal(ULN), and serum transaminase≤2.5×the Upper Limit Of Normal(ULN), serum creatine ≤ 1 x Upper Limit Of Normal(ULN), creatinine clearance rate ≥ 50ml/min,
9. For women of child-bearing age, the pregnancy test results (serum or urine) within 7 days before enrolment must be negative. They will take appropriate methods for contraception during the study until the 8th week post the last administration of study drug. For men (previous surgical sterilization accepted), will take appropriate methods for contraception during the study until the 8th week post the last administration of study drug.
10. Signed and dated informed consent. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure.

Exclusion Criteria:

1. Squamous cell carcinoma (including adenosquamous carcinoma, undifferentiated carcinoma); small cell lung cancer (including small cell and non-small cell mixed lung cancer)
2. Genetic testing for sensitive EGFR mutation or ALK fusion gene is positive didn't accept targeted therapy
3. Symptomatic brain metastases (Patients who have no symptoms and is not needed to receive therapy before 21 days may participate in this trial, but need to be confirmed by MRI\\CT or venography that no hematencephalon symptom);
4. Imaging (CT or MRI) shows that the tumor lesion vessels≤ 5 mm, or in the center of the large vessels tumor;Or show obvious lung empty or necrotic tumor;
5. Uncontrolled hypertension(systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mm Hg) even though two or more than two hypotensive agents application.
6. Patients who suffered from grade II or above myocardial ischemia or myocardial infarction, uncontrolled arrhythmias (including QT interval male ≥ 450 ms, female ≥ 470 ms). Grade III-IV cardiac insufficiency according to New York Heart Association(NYHA) criteria or echocardiography check: left ventricular ejection fraction (LVEF)\<50%.
7. History of pulmonary interstitial diseases or concurrent pulmonary interstitial diseases.
8. Coagulation disfunction（INR\>1.5 o rPT\>Upper Limit Of Normal(ULN)+4s or Activated Partial Thromboplastin Time (APTT) \>1.5 Upper Limit Of Normal(ULN)）, hemorrhagic tendency or receiving the therapy of thrombolysis or anticoagulation.
9. History of clinically significant haemoptysis =\< 2 months (more than 2.5ml or half of one tea spoon of fresh blood per day) prior to registration.
10. History of clinically relevant major bleeding event=\< 3 months.
11. Within 12 months before the first treatment occurs artery / venous thromboembolic events, such as cerebral vascular accident (including transient ischemic attack(TIA), hematencephalon, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc.
12. Known inherited and acquired hemorrhagic and thromboplastic possibility (such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc.)
13. Long-term untreated wounds or fractures.
14. Within 4 weeks of major surgery and/or injures, fractures , ulceration.
15. Significant factors that influence the ingestion and absorption of medicine, (e.g. unable swallow, chronic diarrhea and intestinal obstruction).
16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 6 months.
17. Urine protein≥++, or 24h urine protein quantitation≥1.0g.
18. History of psychiatric drugs abuse and not be abstinent, or dysphrenia.