Anlotinib Hydrochloride Combined With EGFR TKIs in Advanced Non-small Cell Lung Cancer

Inclusion Criteria:

* Participants must have histlogically confirmed stage IV non-small cell lung cancer .
* The initial treatment with gefitinib/icotinib evaluated PR/NC and the efficacy lasted for more than 6 months, then the disease progressed later. (The efficacy was assessed as PD according to the evaluation standard of RECIST1.1)
* At least a measurable lesion that meets the RECIST 1.1 criteria.
* Any gender. Age ≥18 years and ≤75 years
* Life expectancy \>3 months.
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
* Previously, EGFR gene test showed EGFR exon 19 deletion or exon 21 (L858R) mutation, and the gene test showed no T790M mutation before enrollment.
* Adequate organ function: haemoglobin ≥ 90 g/L;neutrophils count ≥1.5×109/L; platelet count ≥ 90 × 109/L; total bilirubin ≤ 1.5 × ULN ;ALT \< 2 × ULN, (ALT \< 5 × ULN, for those with liver metastases);AST \< 2 × ULN, (AST \< 5 × ULN, for those with liver metastases); Cr≤1.5× ULN.
* Echocardiography : LVEF≥50%
* 12-leads electrocardiogram : QTcF\<450ms (man), \<470ms(woman)
* Patient informed consent and signed written consent
* Patient compliance was good and voluntary follow-up, treatment, laboratory testing, and other research steps were performed as planned.

Exclusion Criteria:

* The patient has previously received anti-tumor therapy for EGFR TKIs other than gefitinib and ectinib for lung cancer.
* Patients that cannot detect EGFR gene, or patients with known T790M mutation.
* Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer).
* CT or MRI shows that the tumor lesion is ≤ 5 mm from the large vessel, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor.
* Active brain metastasis, cancerous meningitis, spinal cord compression patients.
* Other active malignancies that require simultaneous treatment.
* Has a history of malignant tumors in the past 5 years.
* Patients with previous anti-tumor treatment-related adverse reactions who have not recovered to NCI-CTC AE≤1.
* Abnormal coagulation ,with bleeding tendency or undergoing thrombolysis or anticoagulant therapy.
* Renal insufficiency: urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g, or creatinine clearance \<60ml / min.
* Severe acute or chronic infection requiring systemic treatment.
* Suffering from severe cardiovascular disease: myocardial ischemia ,myocardial or arrhythmia.
* Clinically significant hemoptysis occurred within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or a clear tendency to hemorrhage.
* Untreated active hepatitis : Hepatitis B or Hepatitis C