A Trial of Anlotinib Combined With Docetaxel in EGFR Mutations Advanced Non Small Cell Lung Cancer Patients

Inclusion Criteria:

• The subjects voluntarily join the study and sign an informed consent form, with goodcompliance and cooperation with follow-up.
• EGFR mutation-positive、ALK mutation-negative；Patients have progressed after receivingEGFR targeted and chemotherapy as first-line treatment.
• Patients who were resistant to EGFR targeted treatment need to receive T790M mutationtest. If the test is positive and Patients have not orally taken osimertinib oralmonertinib, patients need to orally taken osimertinib or almonertinib and beprogressed prior to enrollment.
• ≥ 18 and ≤ 75 years of age; female or male.
• Diagnosed with local advanced and/or metastatic NSCLC (phase IIIB、IIIC or IV) throughHistology or cytology (using the new version of staging announced by the AmericanJoint Committee on Cancer on January 1, 2018), or recurrent non- squamous non-smallcell lung cancer. Noted: failed from prior treatment means(1) progress diseaseconfirmed by definite imageology and clinical evidence during treatment or after thelast treatment; (2) Patients withdrew from treatment because of intolerant adverseevents, the intolerant adverse events refer to≥ level IV hematologic toxicities or ≥level III non-hematologic toxicities or ≥ level 2 damages of major organs such asheart/liver/kidney in CTC AE 4.0.
• There is at least one target lesion that has not received radiotherapy, and it can beaccurately measured by magnetic resonance imaging (MRI) or computed tomography (CT) inat least one direction (the maximum diameter needs to be recorded), where the maximumtumor diameter is >10 mm; the shortest diameter of the lymph node is >15mm.
• Expected survival time: at least 3 months
• ECOG PS：0-1
• The damage caused by other treatments has been recovered (NCI-CTCAE 4.0 versionclassification≤level 1); Radiotherapy (except local palliative radiotherapy)≥ 2 weeks.
• The main organs function are normally, the following criteria are met

1. Blood routine examination criteria should be met (no blood transfusion and bloodproducts within 14 days): HB≥90 g/L; ANC ≥ 1.5×10^9/L; PLT ≥80×10^9/L;
2. Biochemical examinations must meet the following criteria: TBIL<1.5ULN; ALT andAST < 2.5ULN, and for patients with liver metastases < 5ULN; Serum Cr ≤ 1.25ULNor endogenous creatinine clearance > 45ml/min (Cockcroft-Gault formula);

• Women of childbearing potential must have taken reliable contraceptive measures or theresult of serum or urine pregnancy test should be negative within 7 days prior tostudy enrollment, and willing to use and utilize an adequate method of contraceptionthroughout treatment and for at least 8 weeks after the last test drug administration.Man participants should agree to use and utilize an adequate method of contraceptionthroughout treatment and for at least 8 weeks after the last test drug administrationor surgical sterilization.

Exclusion Criteria:

• Squamous carcinoma of lung (including Adenosquamous carcinoma); Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non- small cell lungcancer);
• Have used Anlotinib Hydrochloride、docetaxel before; Postoperative adjuvant therapywith docetaxel is acceptable.
• Imaging (CT or MRI) shows that the distance between tumor lesion and the large bloodvessel is ≤ 5 mm, or there is a central tumor that invades the local large bloodvessel; or there is a significant pulmonary cavity or necrotizing tumor;
• Medical history and combined history：

1. Significant brain metastases, cancerous meningitis, spinal cord compression, orimaging CT or MRI screening for brain or pia mater disease (a patient with brainmetastases who have completed treatment and stable symptoms in 28 days beforeenrollment may be enrolled, but should be confirmed by brain MRI, CT orvenography evaluation as no cerebral hemorrhage symptoms);
2. The patient is participating in other clinical studies.
3. Other active malignancies that require simultaneous treatment;
4. Patients with a history of malignant tumors except for patients with cutaneousbasal cell carcinoma, superficial bladder cancer, cutaneous squamous cellcarcinoma or orthotopic cervical cancer who have undergone a possible curativetreatment and have no disease recurrence within 5 years from the start oftreatment;
5. Patients with previously systemic anti-tumor treatment-related adverse reactions (excluding hair loss) who have not recovered to NCI-CTCAE ≤level 1;
6. Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 secondsor APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic oranticoagulant therapy; Note: Under the premise of prothrombin time internationalnormalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 millionto 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed forpreventive purposes;
7. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g;
8. The effects of surgery or trauma have been eliminated for less than 14 daysbefore enrollment in subjects who have undergone major surgery or have severetrauma;
9. Severe acute or chronic infections requiring systemic treatment;
10. Suffering from severe cardiovascular disease: myocardial ischemia or myocardialinfarction above grade II, poorly controlled arrhythmias (including men with QTcinterval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IVInsufficient function, or cardiac color Doppler ultrasound examination indicatesleft ventricular ejection fraction (LVEF) <50%;
11. Peripheral neuropathy with ≥CTCAE degree 2 currently exists, except for traumacaused;
12. Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (includingpleural effusion, ascites, pericardial effusion) requiring treatment;
13. Long-term unhealed wounds or fractures;
14. Decompensated diabetes or other ailments treated with high doses ofglucocorticoids;
15. Factors that have a significant impact on oral drug absorption, such as inabilityto swallow, chronic diarrhea, and intestinal obstruction;
16. Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3months before enrollment; or significant clinically bleeding symptoms or definedbleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer,baseline fecal occult blood ++ and above, or suffering from vasculitis;
17. Events of arterious/venous thrombosis occurring within 12 months prior toenrollment, such as cerebrovascular accidents (including transient ischemicattacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, andpulmonary embolism;
18. Planned for systemic anti-tumor therapy, including cytotoxic therapy, signaltransduction inhibitors, immunotherapy. Extended-field radiotherapy (EF-RT) wasperformed within 3 weeks before grouping or limited-field radiotherapy to beevaluated for tumor lesions within 2 weeks before grouping;
19. Uncontrollable hypertension with two or more combined treatments (systolic bloodpressure ≥145 mmHg or diastolic blood pressure ≥90 mmHg);
20. Have a history of psychotropic substance abuse and are unable to quit or have amental disorder;

• Physical examination and laboratory examination findings

1. A known history of HIV testing positive or acquired immunodeficiency syndrome (AIDS);
2. untreated active hepatitis (hepatitis b: HBsAg positive and HBV DNA ≥500 IU/ml;Hepatitis c: HCV RNA is positive and liver function is abnormal); Combined withhepatitis b and hepatitis c infection;

• Other factors that may cause the study to be terminated midway according to theresearchers' judgment, such as other serious diseases or severe laboratory testabnormalities or factors that will endanger patients' safety, or family or societyfactors of test data and sample collection.