Epidermal growth factor receptor Tyrosine kinase inhibitor (EGFR TKI) have been approved to treat NSCLC harboring EGFR mutation as first-line therapy. However, the acquired resistance of EGFR-TKI is a common and severe problem.The study explore the superiority of anti-angiogenesis drugs (Apatinib, endostatin, anlotinib) plus EGFR TKI versus single EGFR-TKI.

Non-small-cell lung cancer (NSCLC) is the leading cause from cancer in China. Epidermal growth factor receptor Tyrosine kinase inhibitor (EGFR TKI) have been approved to treat NSCLC harboring EGFR mutation as first-line therapy. However, a large proportion of patients would become acquired resistant of EGFR-TKI after about one year although initially sensitivity. Anti-angiogenesis therapy plus EGFR-TKI has been demonstrated valid and safe in NSCLC patients. Apatinib, endostatin, anlotinib belong to anti-angiogenesis drugs and can inhibit tumor growth. In this study, we plan to recruit NSCLC patients who are assessed as stable disease ( according to RECIST) under treatment of EGFR-TKI. Then, these patients would be divided into two groups: single EGFR-TKI or EGFR-TKI plus anti-angiogenesis drugs. Progression free survival, overall survival and safety are our evaluation events.

Inclusion Criteria:

1. Aged from 18 to 75 years (18 and 75 years are included)Obtain of informed consent.

2. Histologically or cytologically confirmed, inoperable, recurrence or metastasis advanced non-small cell lung cancer (TNM Stage ⅢB or stage Ⅳ), took EGFR-TKI longer than 2 months and appeared Stable disease.

3. At least one measurable lesion (helical CT scan long diameter ≥10mm, meet the requirements of the standard Response Evaluation Criteria In Solid Tumors（RESCIST） version 1.1).

4. Eastern Cooperative Oncology Group（ECOG）Performance Status（PS） :0-2.

5. Life expectancy ≥12 weeks.

6. Adequate bone marrow reserve and organ function as follows:

   • Absolute neutrophils count (ANC) ≥1.5 x 10 to the 9th power/L (band neutrophil and segmented neutrophil), platelets > 100 x 10 to the 9th power/L and Hb≥90g/L.

     • Hepatic: total bilirubin less than or equal to 1.5 times upper limit of normal (ULN).

       • Alkaline phosphatase (AP), alanine transaminase (ALT) and aspartate transaminase (AST) less than or equal to 3.0 times ULN (or less than or equal to 5 times ULN in case of known liver involvement.

         • Renal: Serum Creatinine less than or equal to 1.25 times upper limit of normal (ULN).

7. Females of child-bearing potential must have negative serum pregnancy test. Sexually active males and females (of childbearing potential) willing to practice contraception during the study.

Exclusion Criteria:

1. Do not meet the above criteria.
2. Unhealed toxicity of prior anti-cancer treatment (CTCAE Level 1) or surgery. Uncontrolled hypertension (systolic ≥140mmHg and/or diastolic ≥90mmHg after medication treatment).
3. Clinical uncontrolled active infection, such as acute pneumonia, active hepatitis B or C (prior hepatitis B history, despite medication treatment control or not, HBV DNA≥500copies or ≥100IU/ml), etc.
4. Arterial thrombosis or venous thrombosis in 6 months, or disposition evidence of thrombosis/bleeding in 2 month (despite severity), hemoptysis in 2 weeks (bright red blood, 1/2 teaspoon).
5. Stroke or transient ischemic attack (TIA) in 12 month. Unhealed skin lesions, surgical site, injuries, severe mucous membrane ulcer or bone fracture.
6. Cardiac function evaluation: LVEF <50%, a recent history of MI in 6 months, severe/unstable angina or coronary bypass surgery, or cardiac insufficiency ≥ NYHA 2.
7. Prior other malignant disease in 5 years.
8. Recent active digestive disease such as duodenal ulcers, ulcerative colitis, ileus, ect., intestinal perforation, intestine fistula, or other conditions may lead to gastrointestinal bleeding or perforation which regimented at investigators' discretion.
9. Difficulty swallowing or known malabsorption.
10. A history of organ transplantation and long-term immunosuppressive medication.
11. Take part in new drug clinical trials within one month or taking part in a trial now.
12. Pregnant or lactating woman.
13. Other conditions regimented at investigators' discretion.