Efficacy prediction and prognostic analysis on immunotherapy and TKIs combination treated mRCC by customized tumor-informed ctDNA-MRD.

Abstract

e16513 Background: Around 20–30% of renal cell carcinoma (RCC) cases are metastatic (mRCC) at diagnosis, and 20–40% of patients develop metastases after nephrectomy for localized disease, both linked to a poor prognosis. Tyrosine kinase inhibitors (TKIs), either as monotherapy or in combination with immune checkpoint inhibitors (ICIs), have revolutionized treatment approaches, significantly improving efficacy for advanced mRCC, while still need the increasing importance of precision medicine in clinical practice. Circulating tumor DNA-based minimal residual disease (ctDNA-MRD) detection was considered as a promising, non-invasive tool for therapeutic efficacy monitor. In this study, we applied a customized ctDNA-MRD strategy to assess the outcomes of TKI and TKI + ICI treatments in mRCC patients. Methods: Patients diagnosed with mRCC and undergoing TKI/TKI + ICI combination therapy were recruited. Tumor tissue samples were obtained via biopsy or surgery prior to treatment initiation, and plasma samples were collected at baseline and approximately every three months during therapy. Tissue samples underwent whole-exome sequencing (WES) to identify patient-specific mutations. Based on this analysis, up to 40 highly specific loci were selected to construct a bespoke ctDNA-MRD assay panel for each patient. Plasma samples were subjected to ultra-deep sequencing at 100,000× coverage to assess tumor-derived molecular signals in peripheral blood. Results: The study cohort consisted of 60 mRCC patients, (M: 73.33%, F: 26.67%) enrolled over the past 20 months, and the majority (86.67%) were over 50 years old. The most common metastatic sites included the lungs, bones, and lymph nodes. WES analysis revealed high frequent mutations in genes including VHL (66.10%), PBRM1 (35.59%), TTN (25.42%), SETD2 (23.73%), and ASPA (20.34%), with an average of 185 mutations per patient. Customized ctDNA-MRD panel for 60 patients, encompassing 1,871 unique loci with a mean of 31 loci per panel without overlap; the baseline ctDNA detection rate was 80%, demonstrating the assays high sensitivity. During treatment, a downward trend was observed in the number of detected loci and ctDNA concentration in peripheral blood at baseline (11–1, 6.61 hGE/mL) and follow-up (1, 0.39 hGE/mL), which correlated with treatment response (PR/CR, p < 0.05), while the SD group showed no significant changes. In the long-term follow-up of three PR and one SD patient, dynamic changes in ctDNA-MRD levels effectively indicated disease progression. Conclusions: Customized ctDNA-MRD detection is a highly effective, convenient, reproducible, and non-invasive tool for assessing the efficacy of TKI /TKI + ICI adjuvant therapies in mRCC patients. This approach provides a real-time and sensitive method for therapeutic monitoring, offering significant potential to enhance precision medicine in mRCC management.