The purpose of this study is to evaluate the safety and feasibility of a treatment holiday strategy directed by CD70-targeted immuno-PET/CT in patients with metastatic clear cell renal cell carcinoma (mccRCC). Specifically, the study aims to assess whether patients who achieve both anatomical disease control and metabolic response after 12 months of first-line PD-1/PD-L1 ICI + VEGFR-TKI combination therapy can safely pause their treatment, improve quality of life without compromising therapeutic efficacy.

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.

While intermittent therapy shows promise in maintaining efficacy while mitigating adverse events, conventional CT relies on morphological changes and lacks the sensitivity to distinguish viable tumor tissue from post-treatment fibrosis or necrosis, hindering precise decision-making for treatment cessation. CD70 is a transmembrane protein highly expressed in over 80% of mccRCCs. CD70-targeted immuno-PET/CT, utilizing specific single-domain antibodies, provides a superior molecular imaging tool outperforming FDG-PET and allows for accurate assessment of treatment response to guide intermittent therapy.

In this multi-center, single-arm, phase II trial, mccRCC patients with IMDC favorable or intermediate risk will be enrolled to receive standard first-line ICI plus TKI combination therapy for 12 months (± 1 months) in the absence of disease progression or unacceptable toxicity. After that, patients will be evaluated using both CT (RECIST 1.1) and CD70 immuno-PET/CT (PERCIST criteria). Patients achieving sustained disease control on CT combined with Complete Metabolic Response (CMR) or Partial Metabolic Response (PMR) on CD70 immuno-PET/CT will qualify to pause all systemic treatments and enter treatment holiday. A per-lesion evaluation principle will be applied for baseline heterogeneous lesions. Patients fail to achieve the predefined criteria will continue first-line systemic therapy until disease progression or unacceptable toxicity.

During the treatment holiday, patients will undergo anatomical and molecular monitoring including CT scans every 8-12 weeks and CD70 immuno-PET/CT every 24 weeks. Circulating KIM-1 levels will be longitudinally assessed as an early-warning biomarker. A confirmed clinically meaningful elevation (e.g., ≥ 30% from nadir) may trigger unscheduled or more frequent radiographic evaluations. Original regimen will be immediately restarted upon the occurrence of anatomical progression (RECIST 1.1), metabolic flare (PERCIST), or clinical symptom deterioration.

Peripheral blood, other biological samples, and health-related quality of life questionnaires will be collected at different time points during the trial for future analyses.This study aims to establish a multidimensional decision-making framework to optimize the balance between survival benefits and quality of life in advanced 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