After the second-line treatment of patients with non-T790M mutations, chemotherapy with platinum-containing drugs was used, and chemotherapy-related toxicity was high. Studies have shown that bevacizumab combined with EGFR TKI have a good trend of benefit. This study is aimed to evaluate the efficacy and safety of Anlotinib Hydrochloride combined with first-generation EGFR TKIs as second-line treatment in advanced non-small cell lung cancer . The patients with IV non-small lung cancer have acquired resistance to prior first-generation EGFR TKIs and have non-T790M mutation.

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