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.
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.
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.
Patients with histologically confirmed advanced non-clear cell renal cell carcinoma treated at West China Hospital, Sichuan University, who are scheduled to initiate immune checkpoint inhibitor-based systemic therapy according to routine clinical practice. Eligible histological 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.
Cohort
Prospective
Patient-Specific Tumor-Informed ctDNA Monitoring
Diagnostic testTumor tissue and matched normal blood will undergo genomic analysis to identify patient-specific somatic variants for development of a personalized tumor-informed ctDNA assay. Longitudinal plasma samples will subsequently be analyzed for ctDNA during systemic therapy. The assay is used for research monitoring and does not determine treatment selection.
Progression-Free Survival According to Baseline ctDNA Status
Progression-free survival (PFS) will be defined as the time from initiation of immune checkpoint inhibitor-based systemic therapy to radiographic disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. PFS will be compared between participants with detectable and undetectable baseline ctDNA. The primary effect estimate will be the hazard ratio with its 95% confidence interval.
Objective Response Rate According to Baseline ctDNA Status
Objective response rate (ORR) will be defined as the proportion of participants achieving a best overall response of complete response or partial response according to RECIST version 1.1. ORR will be compared between participants with detectable and undetectable baseline ctDNA.
Overall Survival According to Baseline ctDNA Status
Overall survival will be defined as the time from initiation of immune checkpoint inhibitor-based systemic therapy to death from any cause and will be compared according to baseline ctDNA status.
Disease Control Rate According to Baseline ctDNA Status
Disease control rate will be defined as the proportion of participants achieving complete response, partial response, or stable disease as the best overall response according to RECIST version 1.1 and will be compared according to baseline ctDNA status.
Duration of Response According to Baseline ctDNA Status
Among participants achieving complete or partial response, duration of response will be defined as the time from the first documented objective response until radiographic disease progression or death from any cause, whichever occurs first.
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