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

Patients with unresectable or metastatic non-clear cell renal cell carcinoma who are scheduled to receive immune checkpoint inhibitor-based systemic therapy according to routine clinical practice will be prospectively enrolled. Treatment regimens may include immune checkpoint inhibitor plus targeted therapy, dual immune checkpoint blockade, or immune checkpoint inhibitor monotherapy. Treatment selection will not be determined by this study.

For each participant, tumor tissue and matched normal peripheral blood will be analyzed to identify patient-specific somatic variants and establish a personalized tumor-informed ctDNA assay. Peripheral blood for longitudinal ctDNA monitoring will be collected before treatment, during early treatment, at the first radiographic assessment, during subsequent radiographic evaluations when feasible, and at disease progression or treatment discontinuation.

The primary analyses will compare progression-free survival and objective response rate between patients with detectable and undetectable baseline ctDNA. Secondary analyses will evaluate overall survival, disease control rate, and duration of response. Exploratory analyses will characterize longitudinal ctDNA patterns, including persistently negative, positive-to-negative, persistently positive, and negative-to-positive patterns, and investigate their associations with clinical outcomes, radiographic tumor burden, and the timing of disease progression.

Research ctDNA results will be used for scientific analysis and supportive clinical assessment and will not serve as the primary basis for treatment decisions.

Inclusion criteria

Participants must meet all of the following criteria:

• Age 14 years or older, with no restriction based on sex.
• 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.
• Unresectable or metastatic renal cell carcinoma with at least one measurable lesion according to RECIST version 1.1.
• 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.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and an estimated life expectancy greater than 3 months.
• 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:

• The planned systemic treatment does not contain an immune checkpoint inhibitor and consists only of chemotherapy, targeted therapy, or another non-immunotherapy systemic treatment.
• Untreated, symptomatic, or clinically unstable central nervous system metastases or leptomeningeal metastases.
• 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.
• Major surgery or severe trauma within 4 weeks before enrollment without adequate recovery.
• 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.
• Pregnancy or breastfeeding.
• 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.
• 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.
• 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.