Vorolanib Plus Sintilimab for Advanced Renal Cell Carcinoma After Failure of Prior Immune Checkpoint Inhibitors Based Combination Therapy

Inclusion Criteria:

1. Age ≥18 years and ≤75 years, any gender.

2. Histologically confirmed diagnosis of renal cell carcinoma.

3. Diagnosis of metastatic renal cell carcinoma or TNM stage IV (according to the 2017TNM staging system). Evidence of distant metastasis by imaging or pathology.

4. Prior immune checkpoint inhibitors based combination therapy, dual immunecombination, or immune monotherapy with disease progression, or who have receivedsecond/third line targeted monotherapy, immune monotherapy, or a change inimmune-based combination therapy after failure of one of the above therapies for nomore than 1 month and have completed the washout period. ECOG performance status ≤2.

5. Life expectancy of at least 3 months.

6. Signed informed consent and ability to comply with the protocol-specified visits andprocedures.

7. Agreement to provide tumor tissue and blood specimens required for the study.

8. Adequate organ and bone marrow function as follows: absolute neutrophil count (ANC) ≥1×10^9/L, platelets (PLT) ≥50×10^9/L, hemoglobin (HGB) ≥80g/L; liver function:serum total bilirubin (TBIL) ≤3 times the upper limit of normal (ULN), alanineaminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤5 times ULN, serumalbumin (ALB) ≥20 g/L; renal function: serum creatinine (Cr) ≤3×ULN.

Exclusion Criteria:

1. Pathologically diagnosed with non-renal cell carcinoma, collecting duct carcinoma.

2. First-line treatment with targeted monotherapy, or progression after first-lineimmune checkpoint inhibitors based combination therapy, followed by more than 1month of treatment with targeted therapies, anti-PD-1 antibodies, anti-PD-L1antibodies, anti-PD-L2 antibodies, or anti-CTLA-4 antibodies specifically targetingT cell co-stimulation or checkpoint pathways and/or incomplete washout period.

3. Active brain metastases.

4. Personal history of other malignant tumors within 3 years with a different primarysite or histology than that being evaluated in this study, excluding patients withwell-controlled basal cell carcinoma, squamous cell carcinoma, or cervicalintraepithelial neoplasia.

5. Major surgery or severe trauma within 4 weeks prior to enrollment.

6. Subjects with conditions requiring systemic corticosteroids (>10mg/day prednisone orequivalent) or other immunosuppressive medications within 14 days prior to initialstudy drug administration. Subjects with inactive autoimmune disease are allowed toreceive local, ophthalmic, intra-articular, intranasal, inhaled corticosteroids, oradrenal replacement steroids (>10mg/day prednisone dose or equivalent).

7. Known or suspected active autoimmune disease (congenital or acquired), such asinterstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis,nephritis, thyroiditis, etc. Subjects with type 1 diabetes, thyroid dysfunctionrequiring only hormone replacement therapy, skin diseases (such as vitiligo,psoriasis, or alopecia) that do not require systemic treatment, or conditionsexpected not to recur in the absence of external triggering factors are allowed toparticipate in this study. Known allogeneic organ transplant (excluding cornealtransplant) or allogeneic hematopoietic stem cell transplant.

8. Allergy to any component of monoclonal antibodies.

9. Uncontrolled other severe diseases, including but not limited to:

10. Severe infection in the active or poorly controlled clinical phase;

11. HIV infection (HIV antibody positive);

12. Acute or chronic active hepatitis B (HBsAg positive and HBV DNA >1*103/ml) oracute or chronic active hepatitis C (HCV antibody positive and HCV RNA >15IU/ml);

13. Active pulmonary tuberculosis, etc.

14. NYHA class III-IV congestive heart failure, persistent symptomatic arrhythmia,uncontrolled atrial fibrillation; multiple echocardiographic assessments of leftventricular ejection fraction (LVEF) lower than the lower limit of normal.

15. Uncontrolled hypertension (systolic blood pressure ≥160mmHg and/or diastolic bloodpressure ≥100mmHg);

16. Any arterial thrombosis, embolism, or ischemia in the past 6 months prior toenrollment, such as myocardial infarction, unstable angina, cerebrovascular accidentor transient ischemic attack, etc.;

17. Diseases requiring warfarin (coumarin) anticoagulant therapy;

18. Uncontrolled hypercalcemia (calcium ion >1.5 mmol/L or calcium >12 mg/dL orcorrected serum calcium >ULN), or symptomatic hypercalcemia requiring continuedbisphosphonate therapy;

19. Uncontrolled adrenal insufficiency;

20. History of abdominal fistula, gastrointestinal perforation, or intra-abdominalabscess within the past 6 months;

21. Severe, non-healing wounds or ulcers;

22. Gastrointestinal diseases with impaired gastrointestinal function (such asmalabsorption, ulcerative disease, uncontrollable nausea, vomiting, diarrhea, orsmall bowel resection);

23. Other acute or chronic diseases, mental illnesses, or laboratory abnormalities thatmay lead to the following outcomes: increased risk associated with studyparticipation or drug administration, or interference with interpretation of studyresults, and deemed ineligible for study participation at the discretion of theinvestigator;

24. Pregnant or lactating women.