A Trial of Sintilimab Plus Anlotinib For Metastatic NSCLC After First-Line PD-1 Inhibitor

Inclusion Criteria:

1. The patient voluntarily participated in this study and signed an informed consentform;

2. Gender is not limited, 18-75 years old; ECOG PS score: 0~1; The expected survivaltime is more than 3 months;

3. It is diagnosed as advanced (stage IV) non-small cell lung cancer by cytology orhistology, and the disease has progressed after receiving PD-1 antibody treatment inthe past. According to RECIST 1.1, the efficacy evaluation standard for solidtumors, it has measurable lesions;

4. Provide detectable specimens (tissue or cancerous pleural effusion) for genotypetesting before enrollment, and patients whose EGFR, ALK and ROS1 gene test resultsare all negative;

5. The main organ functions meet the following criteria within 7 days before treatment: a) Blood routine examination standard (under no blood transfusion within 14 days):

• Hemoglobin (HB) ≥9g/dL; ② The absolute value of neutrophils (ANC) ≥ 1.5×109/L; ③ Platelet (PLT) ≥80×109/L b) The biochemical inspection shall meet thefollowing standards:

• Serum total bilirubin (TBIL) ≤ 1.5 × ULN (for patients with Gilbert syndrome, ≤ 3 × ULN); ② Alanine aminotransferase (ALT) and aspartate aminotransferaseAST≤2.5ULN, such as liver metastasis, ALT and AST≤5ULN; ③ Serum creatinine (Cr)≤1.5ULN or creatinine clearance rate (CCr)≥50ml/min; c) Doppler ultrasoundevaluation: left ventricular ejection fraction (LVEF) ≥ lower limit of normal (50%) d) Coagulation function: activated partial thromboplastin time (APTT),international normalized ratio (INR), prothrombin time (PT)≤1.5×ULN;

6. Women of childbearing age should agree to use contraceptive measures (such asintrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; serum or urine pregnancy tests are negativewithin 7 days before study entry, And must be a non-lactating patient; men shouldagree to use contraceptive measures during the study period and within 6 monthsafter the end of the study period;

Exclusion Criteria:

1. Small cell lung cancer (including mixed small cell lung cancer and non-small celllung cancer);

2. Previously received Anlotinib hydrochloride treatment and other immunotherapy:including but not limited to anti-CTLA-4 antibody, anti-OX40 antibody and anti-CD137antibody treatment and other immunotherapy;

3. Those who have previously received sunitinib, sorafenib, famitinib, apatinib,regorafenib and other similar VEGFR-TKI small molecule drugs;

4. Imaging (CT or MRI) shows that the tumor focus is ≤ 5 mm from the large bloodvessels, or there is a central type tumor that invades the local large bloodvessels; or there is obvious lung cavity or necrotic tumor;

5. Untolerable toxicity in previous anti-PD-1/PD-L1 treatments is defined as follows:

1. ≥Level 3 AE related to anti-PD-1/PD-L1; 2) ≥Level 2 immune-related AEs related toanti-PD-1/PD-L1, but AEs that have been relieved or well-controlled after suspensionof anti-PD-1/PD-L1 or steroid therapy are not excluded. Past colitis, encephalitis,myocarditis, hepatitis, uveitis and non-infectious pneumonia are excluded; 3) Anylevel of CNS or eye AE related to anti-PD-1/PD-L1; Note: Patients with previousendocrine AEs can be admitted to the group if they can be stable and asymptomaticunder appropriate replacement therapy.

2. Severe hypersensitivity after administration of other monoclonal antibodies; 6.Medical history and comorbidities

1. Patients with active and symptomatic brain metastases, cancerous meningitis, spinalcord compression, or brain or pia mater diseases found in imaging CT or MRI duringscreening (brain with stable symptoms and treatment completed 28 days beforeenrollment) Patients with metastases can be included in the group, but they need tobe evaluated by MRI, CT or venography to confirm that they have no symptoms ofcerebral hemorrhage);

2. Patients with a history of malignant tumors, basal cell carcinoma of the skin,superficial bladder cancer, squamous cell carcinoma of the skin, or cervical cancerin situ that have undergone possible curative treatment and have not recurred within 5 years after the start of treatment are excluded;

3. There is any active autoimmune disease or a history of autoimmune disease (such asthe following, but not limited to: autoimmune hepatitis, interstitial pneumonia,enteritis, vasculitis, nephritis; subjects need bronchodilators for medicaltreatment Interventional asthma cannot be included); however, the following patientsare allowed to be included in the group: vitiligo, psoriasis, alopecia,well-controlled type I diabetes that do not require systemic treatment, andhypothyroidism with normal thyroid function after replacement therapy;

4. It is necessary to use immunosuppressive agents or systemic therapy to achieve thepurpose of immunosuppression (dose>10mg/day prednisone or other curative hormones),and continue to use within 2 weeks of the first administration;

5. Within 4 weeks before the first administration, any patients with bleeding orbleeding event ≥ CTCAE Grade 3, or unhealed wounds, ulcers or fractures;

6. Those who have previously received radiotherapy, chemotherapy, or surgery, after thecompletion of the treatment (last medication), less than 4 weeks from the firstadministration, less than 5 drug half-lives of oral targeted drugs; or less than 14days of oral fluorouracil drugs, mitogen Those who have been less than 6 weeks of Cand nitrosourea; those whose adverse events (except for hair loss) caused byprevious treatment have not recovered to ≤ CTCAE 1 degree;

7. Abnormal blood coagulation function (INR>1.5 or prothrombin time (PT)>ULN+4 secondsor APTT>1.5 ULN), have bleeding tendency or are receiving therapeutic thrombolysisor anticoagulation therapy; Note: in prothrombin The use of anticoagulant drugs forpreventive purposes is permitted provided that the international normalized ratio oftime (INR) ≤ 1.5.

8. Renal insufficiency: Urine routine test indicates urine protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g;

9. Uncontrollable hypertension (systolic blood pressure ≥150 mmHg or diastolic bloodpressure ≥100 mmHg, despite the best medical treatment);

10. Unstable angina, myocardial infarction, grade ≥2 congestive heart failure, orarrhythmia requiring treatment (including QTc≥480ms) occurred within 6 months of thefirst administration;

11. Active or uncontrolled serious infection (≥CTC AE grade 2 infection);

12. Liver cirrhosis, decompensated liver disease, active hepatitis* or chronic hepatitisrequire antiviral treatment;

• Active hepatitis (hepatitis B reference: HBsAg positive, and the HBV DNA testvalue exceeds the upper limit of normal; hepatitis C reference: HCV antibodypositive, and the HCV virus titer test value exceeds the upper limit of normal);

13. HIV positive or active tuberculosis;

14. Diabetes is poorly controlled (fasting blood glucose ≥ CTCAE level 2);

15. Have received a preventive vaccine or attenuated vaccine within 4 weeks before thefirst administration;

16. Subjects who have undergone major surgery or severe trauma have had less than 14days of elimination of the effects of surgery or trauma before enrollment;

17. Severe cardiovascular disease: Myocardial ischemia or myocardial infarction abovegrade II, poorly controlled arrhythmia (including QTc interval ≥450 ms for men and ≥470 ms for women); according to NYHA standards, grade Ⅲ～Ⅳ Insufficiency, or cardiaccolor Doppler ultrasound examination reveals that the left ventricular ejectionfraction (LVEF) is less than 50%;

18. Peripheral neuropathy with ≥CTCAE degree 2 currently exists, except for trauma;

19. Respiratory syndrome (≥CTC AE Grade 2 dyspnea), serous effusion (including pleuralfluid, ascites, and pericardial effusion) that need treatment;

20. There are factors that significantly affect the absorption of oral drugs, such asinability to swallow, chronic diarrhea, and intestinal obstruction;

21. Clinically significant hemoptysis (more than 50ml of hemoptysis per day) occurredwithin 3 months before enrollment; or significant clinically significant bleedingsymptoms or clear bleeding tendency, such as gastrointestinal bleeding, hemorrhagicgastric ulcer, fecal occult blood at baseline ++ and above, or suffer fromvasculitis, etc.;

22. Arterial/venous thrombosis events that occurred within 6 months, such ascerebrovascular accidents (including temporary ischemic attacks, cerebralhemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism;

23. Participated in other anti-tumor drug clinical trials within 4 weeks beforeenrollment or planned systemic anti-tumor therapy within 4 weeks before grouping orduring this study medication period, including cytotoxic therapy, signaltransduction inhibitor, immunotherapy ( Or have used mitomycin C) within 6 weeksbefore receiving the trial drug treatment. Expansion-field radiotherapy (EF-RT)within 4 weeks before grouping or limited-field radiotherapy for tumor lesions to beassessed within 2 weeks before grouping; 7. According to the judgment of theinvestigator, the patient may have other factors that may cause the study to beterminated halfway, such as other serious diseases or severe laboratoryabnormalities or other factors that will affect the safety of the subjects, or testdata And the family or society of the sample collection.