Pre-screening Inclusion Criteria:
1. Male or female subjects aged ≥ 18 years at time of signing informed consent
2. Locally advanced (not amenable to curative surgery or radiation therapy) or metastatic RCC (American Joint Committee on Cancer \[AJCC\] Stage IV)
3. Favorable or intermediate risk as per International Metastatic RCC Database Consortium (IMDC) criteria
4. Eastern Cooperative Oncology Group performance status 0 or 1
5. Karnofsky Performance Status (KPS) grade ≥ 70%
6. Adequate organ and bone marrow function meeting all laboratory criteria:
Ⅰ. Absolute neutrophil count (ANC) ≥ 1.5 × 10³/μL (≥ 1.5 GI/L); Platelet count ≥ 100 × 10³/μL (≥ 100 GI/L); Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
Ⅱ. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 × upper limit of normal. Total bilirubin ≤ 1.5 × the upper limit of normal (≤ 3 mg/dL \[≤ 51.3 μmol/L\] if Gilbert's syndrome)
Ⅲ. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min using the Cockroft-Gault formula.
7. Capacity to comprehend and comply with protocol requirements, with documented informed consent signed
8. Contraception agreement for sexually active fertile participants and partners to use of medically accepted methods during study and continue for 5 months after last treatment
9. Negative pregnancy status at screening for women of childbearing potential
Pre-screening Exclusion Criteria:
1. Highly malignant pathology
2. Prior systemic therapy for advanced RCC
3. Poor risk as per International Metastatic RCC Database Consortium (IMDC) criteria
4. ECOG performance status \>1
5. Karnofsky Performance Status (KPS) \<70%
6. Inadequate organ and bone marrow function
7. Bulky or symptomatic disease or hepatic metastases
8. Active brain metastases or leptomeningeal disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before the start of treatment.
9. Concurrent or prior invasive malignancies that could confound efficacy assessment, except adequately treated non-melanoma skin cancer, superficial bladder cancer or carcinoma in situ of the cervix/breast with curative therapy \>3 years ago.
10. Uncontrolled hypertension (\>150/100 mmHg despite optimal therapy)
11. Uncontrolled comorbidities within 6 months including but not limited to: clinically significant cardiovascular disorders, gastrointestinal disorders with high risk of perforation or fistula formation, significant hematuria, hematemesis, hemoptysis, or major bleeding history, severe infections, severe autoimmune diseases (e.g., systemic lupus erythematosus, immune pneumonitis), active HIV, HBV, or HCV infections.
12. Major surgery within 4 weeks with unhealed wounds or planned surgery during study
13. Concomitant use of drugs or substances affecting activity or pharmacokinetics of investigational products
14. Hypersensitivity to any component of study drugs
15. Chronic or concurrent immunosuppressive therapy, except Inhaled/topical steroids
16. Medical/psychiatric/social conditions compromising protocol compliance
17. Pregnancy, lactation, or refusal of contraception during and for 5 months post-treatment
18. Inability to undergo PET/CT or oral drug administration
Main-screening Inclusion Criteria:
1. Patient must receive≥12 months of first line treatment with the combination of PD-1/PD-L1 ICI and VEGFR-TKI, and have not experienced a toxicity that prevents them from continuing on therapy.
2. Patients must achieve complete metabolic response (CMR) or partial metabolic response (PMR) on PET/CT within 24 months of the combination treatment with PD-1/PD-L1 ICI and VEGFR-TKI.
3. Favorable or intermediate risk as per International Metastatic RCC Database Consortium (IMDC) criteria
4. Eastern Cooperative Oncology Group performance status 0 or 1
5. Karnofsky Performance Status (KPS) grade ≥ 70%
6. Adequate organ and bone marrow function meeting all laboratory criteria:
Ⅰ. Absolute neutrophil count (ANC) ≥ 1.5 × 10³/μL (≥ 1.5 GI/L); Platelet count ≥ 100 × 10³/μL (≥ 100 GI/L); Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
Ⅱ. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 × upper limit of normal. Total bilirubin ≤ 1.5 × the upper limit of normal (≤ 3 mg/dL \[≤ 51.3 μmol/L\] if Gilbert's syndrome)
Ⅲ. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min using the Cockroft-Gault formula.
7. Capacity to comprehend and comply with protocol requirements, with documented informed consent signed
8. Contraception agreement for sexually active fertile participants and partners to use of medically accepted methods during study and continue for 5 months after last treatment
9. Negative pregnancy status at screening for women of childbearing potential
Main-screening Exclusion Criteria:
1. Failure to complete ≥12 months of first-line PD-1/PD-L1 + VEGFR-TKI therapy due to unmanageable toxicity or other reasons
2. Failure to achieve CMR or PMR on PET/CT within 24 months after combination therapy; new metastatic lesions or disease progression on PET/CT.
3. Poor risk as per International Metastatic RCC Database Consortium (IMDC) criteria
4. ECOG performance status \>1
5. Karnofsky Performance Status (KPS) \<70%
6. Inadequate organ and bone marrow function
7. Uncontrolled hypertension (\>150/100 mmHg despite optimal therapy)
8. Uncontrolled comorbidities including but not limited to: clinically significant cardiovascular disorders, gastrointestinal disorders with high risk of perforation or fistula formation, significant hematuria, hematemesis, hemoptysis, or major bleeding history, severe infections, severe autoimmune diseases (e.g., systemic lupus erythematosus, immune pneumonitis), active HIV, HBV, or HCV infections.
9. Medical/psychiatric/social conditions compromising protocol compliance
10. Pregnancy, lactation, or refusal of contraception during study period.
11. Inability to undergo PET/CT or oral drug administration
Withdrawal Criteria:
1. Disease progression with unsatisfactory efficacy, or occurrence of intercurrent illnesses during treatment or follow-up period.
2. Occurrence of severe treatment-related adverse reactions.
3. Laboratory test results indicating critical safety values.
4. Voluntary withdrawal of informed consent by the patient.
5. Investigator's judgment that withdrawal is in the subject's best interest.
6. Pregnancy during the trial period.
7. Wrong Enrollees: deviation of inclusion or exclusion criteria.
8. Poor patient compliance.
9. Loss to follow-up or death during the trial period.
