Personalized ctDNA Monitoring for Predicting Immunotherapy Outcomes in Advanced Non-Clear Cell Renal Cell Carcinoma

Patient-Specific Circulating Tumor DNA Monitoring for Prediction of Immunotherapy Response and Prognostic Stratification in Advanced Non-Clear Cell Renal Cell Carcinoma: A Prospective Observational Cohort Study

This is a prospective, non-interventional observational cohort study evaluating the clinical utility of patient-specific circulating tumor DNA (ctDNA) monitoring in patients with advanced non-clear cell renal cell carcinoma (nccRCC) receiving immune checkpoint inhibitor-based systemic therapy. Tumor-informed personalized ctDNA assays will be developed based on tumor tissue and matched normal blood samples, and ctDNA will be longitudinally assessed at predefined time points during treatment. The primary objectives are to evaluate the associations of baseline ctDNA status with progression-free survival and objective response rate. Secondary and exploratory analyses will assess overall survival, disease control, duration of response, longitudinal ctDNA dynamics, radiographic tumor burden, and molecular progression.

Inclusion Criteria:

Participants must meet all of the following criteria:

1. Age 14 years or older, with no restriction based on sex.
2. Histologically confirmed renal cell carcinoma classified as non-clear cell renal cell carcinoma. Immunohistochemical or molecular testing may be used when necessary to establish the histological subtype. Eligible subtypes include papillary renal cell carcinoma, chromophobe renal cell carcinoma, TFE3-rearranged renal cell carcinoma, FH-deficient renal cell carcinoma, collecting duct carcinoma, renal medullary carcinoma, and other rare non-clear cell renal cell carcinoma subtypes.
3. Unresectable or metastatic renal cell carcinoma with at least one measurable lesion according to RECIST version 1.1.
4. Scheduled, according to routine clinical care, to initiate immune checkpoint inhibitor-based systemic therapy, including an immune checkpoint inhibitor combined with targeted therapy, dual immune checkpoint blockade, or immune checkpoint inhibitor monotherapy. The number of previous lines of systemic therapy is not restricted, provided that prior treatment history, specific regimens, and best responses can be adequately documented.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and an estimated life expectancy greater than 3 months.
6. Ability and willingness to provide written informed consent and comply with protocol-specified sample collection, examinations, and follow-up.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded:

1. The planned systemic treatment does not contain an immune checkpoint inhibitor and consists only of chemotherapy, targeted therapy, or another non-immunotherapy systemic treatment.
2. Untreated, symptomatic, or clinically unstable central nervous system metastases or leptomeningeal metastases.
3. Another active malignancy of a different primary site or histological type within the previous 3 years, except adequately controlled malignancies such as papillary thyroid carcinoma, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical carcinoma in situ.
4. Major surgery or severe trauma within 4 weeks before enrollment without adequate recovery.
5. Uncontrolled severe infection or another serious comorbidity, including active tuberculosis, active hepatitis B or C, severe cardiac insufficiency, persistent symptomatic arrhythmia, uncontrolled hypertension, or serious cardiovascular or cerebrovascular events such as myocardial infarction, unstable angina, or cerebrovascular accident within 6 months before enrollment.
6. Pregnancy or breastfeeding.
7. Severe psychiatric, cognitive, or behavioral impairment that prevents understanding of the study, provision of required samples, or completion of protocol-specified examinations and follow-up.
8. Failure to establish a patient-specific ctDNA monitoring panel because of inadequate tumor tissue quantity or quality, inability to identify suitable patient-specific somatic variants, or other technical reasons.
9. Any other condition that, in the investigator's judgment, may increase the risks associated with study participation, interfere with interpretation of the study results, or compromise protocol compliance.