Anlotinib Combination With Vinorelbine in the HER2- Advanced Breast Cancer

Inclusion Criteria:

• 1. Patients voluntarily participated in the study and signed informed consent;
• 2. Women aged 18 or older;
• 3. The number of treatment lines shall not exceed 4 lines;
• 4. Patients with locally advanced or metastatic breast cancer diagnosed asHER2-negative by molecular typing;
• 5. Enrolled patients were HER2-negative breast cancer patients who had failed to priortaxane and/or anthracycline therapy, or patients with hormone receptor-positiveHER2-negative advanced breast cancer who had progressed with at least prior first-lineendocrine therapy;
• 6. ECOG score is 0 or 1, and the expected survival is not less than 3 months;
• 7. Patients with measurable lesions as defined in RECIST1.1 criteria;
• 8. The main organs function well, and the laboratory test indexes meet the followingrequirements:(1) Routine blood test (no blood transfusion or hematopoietic stimulatingfactor was used within 7 days before screening) :① Hemoglobin (HB) ≥ 90g/L;② Absoluteneutrophil count (ANC) ≥1.5×109/L;③ Platelet (PLT) ≥ 80×109/L;(2) Blood biochemicaltest (no blood transfusion or albumin within 7 days before screening) :① ALT and AST ≤2.5 × ULN (liver/bone metastasis ≤5 × ULN; Bone metastases ≤5 ULN);② Serum totalbilirubin (TBIL) ≤1.5 × ULN;③ Serum Cr≤1.5×ULN or creatinine clearance ≥60 mL /min;(3)Coagulation function test:① Activated partial thrombin time (APTT), internationalstandardized ratio (INR), prothrombin time (PT) ≤ 1.5×ULN;② Doppler ultrasoundassessment: left entricular ejection fraction (LVE F)≥ 50%;
• 9. The patient has the ability to take medication orally;
• 10. Any toxic side effects of previous chemotherapy have been recovered to ≤CTCAE1 orbaseline level;
• 11. Women of reproductive age must agree to use a highly effective method ofcontraception during the study period and for 6 months after the last administrationof the study drug; Negative serum or urine pregnancy test within 7 days prior to studyenrollment and must be non-lactating subjects;

Exclusion Criteria:

• 1. Prior treatment with bevacizumab, anlotinib and other antiangiogenic agents;
• 2. Patients who had previously used Vinorelbine with an interval time of less than 6months from the end of medication;
• 3. Interval of less than 3 weeks after radiotherapy or chemotherapy; The intervalafter endocrine therapy was less than 1 week;
• 4. Associated diseases/history;(1) Clinically significant hemoptysis occurred within 3months before enrollment (hemoptysis > 50ml per day); Or bleeding symptoms ofsignificant clinical significance or a clear bleeding tendency, such asgastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occultation andabove, or suffering from vasculitis, etc.;(2) Arteriovenous thrombosis events occurredwithin 6 months before enrollment, such as cerebrovascular accident (includingtemporary ischemic attack), deep venous thrombosis (except those who had been curedafter intravenous catheterization due to chemotherapy) and pulmonary embolism,etc.;(3) hypertension, which cannot be well controlled by antihypertensive drugtherapy (systolic blood pressure & GT; 140 mmHg or diastolic pressure > 90 mmHg);During the first 6 months of randomization, myocardial infarction, severe/unstableangina, NYHA grade 2 or higher cardiac dysfunction, clinically significant ventriculararrhythmias or ventricular arrhythmias, and symptomatic congestive heart failure;(4)Interstitial lung disease, non-infectious pneumonia or uncontrollable systemicdiseases (e.g., diabetes, pulmonary fibrosis and acute pneumonia);(5) Renalinsufficiency: urine protein ≥ ++ indicated by routine urine examination, or confirmed 24-hour urine protein level ≥1.0g;(6) History of live attenuated vaccine vaccinationwithin 28 days prior to initial study administration or expected live attenuatedvaccine vaccination during study period;(7) human immunodeficiency virus (HIV)infection or known acquired immunodeficiency syndrome (AIDS); Active hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/ mL; Hepatitis C, defined as hcV-RNA higherthan the lower limit of assay) or co-infection with hepatitis B and c;(8) Severeinfection, including but not limited to bacteremia and severe pneumonia requiringhospitalization, occurred within 4 weeks before the first administration; Active CTCAEgrade 5.0≥2 infection requiring systemic antibiotic treatment within 2 weeks prior toinitial administration or unexplained fever during screening/prior to initialadministration > 38.5°C (according to the investigator's judgment, fever caused bytumor can be included in the group); Evidence of active tuberculosis infection within 1 year before administration;
• 5. Have been diagnosed with any other malignant tumor within 3 years prior to enteringthe study;
• 6. Thyroid dysfunction;
• 7. Major operations were performed within 28 days before enrollment, and minoroperations were performed within 14 days before enrollment;
• 8. Subjects who have received or are planning to receive allogeneic bone marrowtransplantation or solid organ transplantation;
• 9. Peripheral neuropathy ≥ grade 2; Patients with active brain metastases, cancerousmeningitis, spinal cord compression, or diseases of the brain or pia meningiae foundby imaging CT or MRI examination at the time of screening (patients with brainmetastases who had completed treatment 14 days before enrollment and had stablesymptoms could be enrolled, but were confirmed to have no symptoms of cerebralhemorrhage by craniocerebral MRI, CT or venography evaluation);
• 10. There are significant factors affecting oral drug absorption, such as inability toswallow, chronic diarrhea, and the presence of clinically significant intestinalobstruction.
• 11. Female subjects who are pregnant, breast-feeding, or planning to become pregnantduring the study period.
• 12. Patients with other serious physical or mental disorders or abnormal laboratorytests that may increase the risk of study participation or interfere with studyresults, and who are considered unsuitable for study participation by theinvestigator.