CD70-Targeted Imaging-Guided Pause of Therapy in Metastatic Clear Cell RCC

Inclusion Criteria:

STEP0: At Treatment Initiation

1. Male or female subjects aged ≥ 18 years
2. Locally advanced (not amenable to curative surgery or radiation therapy) or metastatic RCC (American Joint Committee on Cancer \[AJCC\] Stage IV)
3. Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype
4. Favorable or intermediate risk as per International Metastatic RCC Database Consortium (IMDC) criteria
5. Karnofsky Performance Status (KPS) grade ≥ 70%
6. At least one measurable lesion on CT per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
7. At least one high-uptake target lesion on CD70-targeted immuno-PET/CT per Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) version 1.0
8. If CD70-negative lesions (visible on CT but lacking CD70 avidity on PET/CT) are present at baseline, they must meet ALL the following conditions: cannot be target lesions, cannot be located in major involved organs, must be ≤ 3 in number, and must account for ≤ 30% of the total tumor burden
9. Adequate organ and bone marrow function meeting all laboratory criteria:

   * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; Platelet count ≥ 100 × 10\^9/L; Hemoglobin ≥90 g/L
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 × upper limit of normal(ULN) (or ≤ 5 × ULN if hepatic metastases are present). Total bilirubin ≤ 1.5 × ULN (≤ 3 mg/dL if Gilbert's syndrome)
   * Serum creatinine ≤ 2.0 × ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min using the Cockcroft-Gault formula
10. Capacity to comprehend and comply with protocol requirements, with documented informed consent signed
11. Contraception agreement for sexually active fertile participants and partners to use medically accepted methods during the study and continue for 5 months after last treatment
12. Negative pregnancy status at screening for women of childbearing potential

STEP1: At 12-Month Evaluation

1. Patient met all eligibility criteria outlined above
2. Patient must receive 12 months (±1m) of first line PD-1/PD-L1 ICI + VEGFR-TKI therapy, without permanent discontinuation of both agents due to unmanageable toxicity
3. Patient must have completed an CD70-targeted immuno-PET/CT scan at 12m (±1m) from start of initial therapy
4. Patients must meet one of the following criteria:

   * Eligible for treatment discontinuation: For CD70-Positive Lesions: Sustained Disease Control (Complete Response \[CR\], Partial Response \[PR\], or Stable Disease \[SD\]) on CT for ≥ 12 weeks per RECIST 1.1, AND achieved Complete Metabolic Response (CMR) or Partial Metabolic Response (PMR) on CD70 immuno-PET/CT per PERCIST 1.0 criteria; For CD70-Negative Lesions (If present at baseline): Must achieve a deep anatomical response, defined as Complete Response (CR) or Partial Response (PR) on CT, maintained for ≥ 12 weeks per RECIST 1.1
   * Treatment continuation: not meeting criteria above

Exclusion Criteria:

STEP0: At Treatment Initiation

1. Prior systemic therapy for advanced RCC
2. Poor risk as per International Metastatic RCC Database Consortium (IMDC) criteria
3. Karnofsky Performance Status (KPS) \<70%
4. Inadequate organ and bone marrow function
5. Active brain metastases or leptomeningeal disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) who are clinically stable without progression prior to treatment
6. Concurrent or prior invasive malignancies within the past 5 years, except adequately treated in situ/superficial cancers (e.g., non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix/breast)
7. Presence of uncontrolled major comorbidities or recent severe illnesses within 6 months, including but not limited to: uncontrolled hypertension, clinically significant cardiovascular disease, GI disorders with high risk of perforation/fistula, significant hematuria, hematemesis, hemoptysis, major bleeding history, severe active infections (including active HIV, HBV, or HCV), or severe autoimmune diseases (e.g., systemic lupus erythematosus, immune pneumonitis)
8. Life expectancy \< 6 months
9. Known allergy or hypersensitivity to the CD70 imaging agent or any of its excipients
10. Severe hepatic or renal insufficiency, or inability to tolerate PET/CT examination
11. Medical/psychiatric/social conditions compromising protocol compliance
12. Pregnancy, lactation, or refusal of contraception during and for 5 months post-treatment

STEP1: At 12-Month Evaluation

1. Failure to complete 12 months(±1m) of first-line PD-1/PD-L1 + VEGFR-TKI therapy due to unmanageable toxicity or disease progression
2. Failure or inability to undergo CD70-targeted immuno-PET/CT scan at the 12-month evaluation timepoint
3. Unacceptable clinical deterioration or investigator discretion indicating that a treatment holiday is not in the best interest of the patient