PET/CT-Directed Free of Therapy for Metastatic RCC Patients With IMDC Favorable or Intermediate Risk

An Open-label, Investigator-initiated, Single Arm, Exploratory Phase 2 Trial Evaluating the Feasibility and Efficiency of PET/CT Directed Free of Therapy Used for Metastatic and Advanced Renal Cell Carcinoma

This phase 2 trial aims to test the feasibility and efficiency of PET/CT-directed treatment interruption strategy in metastatic renal cell carcinoma patients with IMDC favorable/intermediate risk who achieve complete (CMR) or partial metabolic response (PMR) after ≥12 months of first-line PD-1/PD-L1 Immune checkpoint inhibitor (ICI)+ VEGFR-tyrosine kinase inhibitor (TKI) therapy. It helps figure out whether PET/CT can safely direct treatment pause as well as explores a new individualized treatment option based on metabolic imaging for RCC patients.

Current first-line therapy for advanced renal cell carcinoma (RCC) combines tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICIs). Although effective, continuous treatment often results in cumulative toxicities, significant financial burdens, and potential overtreatment for patients.

To improve such limitations, intermittent therapy strategies has gained more attention. However, existing approaches are constrained by insufficient induction periods (<12 months) that may compromise treatment depth, and reliance on anatomic CT criteria (RECIST 1.1) which cannot reliably differentiate residual active tumor from treatment-related fibrosis/necrosis. PET/CT quantifies tumor metabolic activity via standardized uptake values (SUV), enabling early molecular-level response assessment per PERCIST 1.0 criteria, thus shows promising prospects.

This trial implements a two-stage screening approach. During the pre-screening period, eligible unresectable/metastatic RCC patients with IMDC low/intermediate risk sign the Pre-screening Consent Form to receive ≥12 months of standard ICI+TKI therapy. Consolidative surgery and consolidative radiotherapy during combination therapy are permitted. Patients achieving complete metabolic response (CMR) or partial metabolic response (PMR) on PET/CT within 24 months undergo main screening. Those qualifying sign the Informed Consent Form (ICF), discontinue both agents and enter a closely monitored treatment holiday. During this phase, serial imaging (CT with supplemental PET/CT when indicated) will be performed every 12 ± 1 weeks. Therapy will be restarted immediately if any of the following occur:

• A ≥10% increase in the sum of the longest diameters (SLD) of target lesions from nadir, concurrent with a ≥30% increase in the peak standardized uptake value normalized to lean body mass (SULpeak) relative to baseline;
• New lesion with SULpeak exceeding liver background.

Peripheral blood and other biological samples from participants at different time points during the trial will be collected for future analyses. The primary endpoint is progression-free survival (PFS) rate at 24 months from treatment initiation. Secondary endpoints include duration of response after interruption, objective response rate after restarting therapy, safety (CTCAE v5.0-graded adverse events), patient-reported outcomes and cost-effectiveness. This study pioneers metabolic imaging to guide intermittent therapy in mRCC patients, utilizing extended induction and dual anatomic/metabolic restart thresholds to optimize risk-benefit balance while reducing treatment burden.

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.