58 Baseline Peripheral TCR Diversity as a Biomarker of Response to First-line Immunotherapy in Metastatic Clear Cell Renal Cell Carcinoma

Background In metastatic clear cell renal cell carcinoma (ccRCC), robust biomarkers of immunotherapy response remain lacking to select first-line treatment strategies. The peripheral T-cell receptor (TCR) repertoire reflects the systemic adaptive immune landscape and potential antitumor immune response. We investigated whether baseline peripheral TCR diversity was associated with outcome in patients receiving first-line dual immune checkpoint blockade (dual IO) or immunotherapy combined with a tyrosine kinase inhibitor (IO-TKI). Methods Baseline peripheral blood samples were prospectively collected (NCT04932525). Peripheral blood mononuclear cells were profiled by 5’ single-cell V(D)J sequencing (10X Genomics) and TCR clonotypes reconstructed using the scRepertoire package. Repertoire diversity was quantified using Hill q0 and Hill q1, corresponding respectively to clonotype richness, defined as the number of distinct clonotypes, and effective diversity, reflecting the relative abundance of dominant clonotypes. Associations between baseline TCR diversity and objective response according to RECIST and progression-free survival (PFS) were evaluated. Hill scores were analysed according to median-based stratification and as continuous variables. Rarefaction-based sensitivity analyses accounted for differences in sampling depth. Results Among 18 evaluable patients (9 dual IO, 9 IO-TKI), 13 (72%) achieved an objective response, including 6 (33%) in the dual IO cohort and 7 (39%) in the IO-TKI cohort. Across treatment arms, responders had numerically lower baseline TCR diversity than non-responders across all Hill metrics, although differences were not statistically significant (median Hill q0: 2310 vs 3332, p = 0.14; Hill q1: 879 vs 3248, p = 0.29). When stratified by treatment arm, this pattern was more evident in the dual IO subgroup, where responders had markedly lower diversity, with the strongest signal observed for Hill q1 (median Hill q0: 2379 vs 3332, p = 0.26; Hill q1: 786 vs 3248, p = 0.048). No difference was observed in the IO-TKI subgroup. At a median follow-up of 23.9 months, higher baseline Hill q1 values were associated with shorter PFS in the overall cohort. Median PFS was not reached in the Hill q1-low group versus 4.6 months in the Hill q1-high group (log-rank p = 0.007); continuous Hill q1 was also significantly associated with increased progression risk (HR 2.21, 95% CI 1.14-4.27, p = 0.019). Overall survival analyses showed directionally consistent trends towards improved outcomes with lower Hill q1 scores but were limited by event number. Limited sample size precluded subgroup analyses for survival. Conclusions Baseline peripheral TCR diversity may reflect clonal expansion states and impact immunotherapy outcome in metastatic ccRCC, notably in patients treated with dual IO. These findings support further investigation of peripheral TCR profiling as a non-invasive biomarker of checkpoint inhibitor sensitivity in metastatic ccRCC. DOD CDMRP Funding no