Baseline histopathologic biomarker for predicting frontline immunotherapy combination outcomes in metastatic clear cell renal cell carcinoma (mccRCC).

e16539 Background: The treatment landscape of mccRCC has evolved in recent years, with immune checkpoint inhibitor (ICI) combinations currently serving as the frontline backbone therapy. However, there remains a lack of robust biomarkers to predict treatment outcomes with ICI combinations. Previously, we demonstrated favorable outcomes with nivolumab monotherapy in previously treated mccRCC patients using hematoxylin and eosin (H&E)-based scoring of tumor infiltrating immune cells (TIL plus ) and necrosis (Deutsch, Cell Rep Med , 2023). Herein, we investigated the utility of this biomarker in the context of first-line ICI combinations in mccRCC. Methods: We conducted a retrospective analysis of mccRCC patients treated at our institution (2013–2024). Eligibility criteria included: confirmed ccRCC histology, metastatic disease, treatment with first-line ICI combinations (dual ICI or ICI plus tyrosine kinase inhibitor [TKI]), and availability of H&E-stained slides from metastatic lesions (excluding brain) prior to treatment. Using previously published methodology, TIL plus scores were generated by assessing the mononuclear immune infiltrate, including tumor infiltrating lymphocytes, macrophages, plasma cells, and other associated immune cells. TIL plus was scored as ‘‘0’’ (no immune infiltrate identified interfacing with tumor) or ‘‘1’’ (immune infiltrate involving tumor was present). Necrosis was scored as “0” if necrosis involved ≤10% surface area and as a “1” if > 10%. Overall survival (OS) and progression-free survival (PFS) were calculated from ICI initiation using the Kaplan-Meier method. Associations between survival outcomes and the TIL plus and necrosis scores were assessed. Results: A total of 35 patients were included, receiving first-line ICI combinations: ICI+ICI (n = 12) and ICI+TKI (n = 23). Across all patients, OS and PFS were significantly improved in those with TIL plus 1 compared to TIL plus 0 (p = 0.04, log-rank test, and p = 0.01, Gehan-Breslow-Wilcoxon test, respectively) (Table). Necrosis scores did not associate with OS or PFS. Conclusions: Baseline assessment of TIL plus on H&E may serve as a novel biomarker for predicting outcomes to first-line ICI combinations in patients with mccRCC. Incorporation of this biomarker into a prospective clinical trial will be needed for validation. Group N Median OS (months) P-value Median PFS (months) P-value TIL plus group TIL plus 1 17 NR P=0.04 23.7 P=0.01 TIL plus 0 18 24.0 9.9 NR = not reached.