Abstract 7155: A PD-L1-independent phenotype uncovers responders to combined therapy with immune checkpoint inhibitors in kidney cancer

Abstract Immunotherapy with immune checkpoint inhibitors (ICI) has substantially improved the treatment of advanced renal cell carcinoma (aRCC). Since treatment effects vary among patients, identifying biomarkers to predict response is crucial for optimizing clinical management. Expression of programmed death ligand 1 (PD-L1) is associated with better response to ICI treatment, but is not a valid biomarker. To advance patient stratification for aRCC, we analyzed molecular and clinical data from the JAVELIN Renal 101 (n=726) and IMmotion151 (n=823) trials, both of which compared a combination of PD-L1 inhibitors and anti-angiogenic treatments with sunitinib monotherapy. In JAVELIN Renal 101, we found correlations between genes and progression-free survival (PFS) in PD-L1-positive tumors treated with sunitinib. These associations were independent of variations in the proportion of PD-L1-positive immune cells present in the tumors. Clustering of PD-L1-positive tumors based on PFS-related genes revealed an IMmune CHeckpoint Inhibitor-responsive Phenotype (IMCHIP). In PD-L1-positive tumors with IMCHIP, combined therapy with ICI led to significantly longer PFS relative to sunitinib (13.3 months vs. 4.4 months median PFS), while in PD-L1-positive tumors without IMCHIP, PFS was comparable for both treatments (11.1 months). By de-correlating gene expression measurements from PD-L1 expression, the clustering could be extended to PD-L1-negative tumors resulting in two groups (aRCC1/2) that were independent of PD-L1 status. Stratification based on aRCC1/2 and PD-L1 status allowed treatment effects to be categorized into four groups. A significant difference in PFS between treatments arms was only observed in patients with tumors of type aRCC2/PD-L1-positive, which corresponded to the IMCHIP profile and covered 32.4% of JAVELIN Renal 101. These findings could be validated in the IMmotion151 trial, where IMCHIP represented 20% of the cohort. Compared to other biomarkers currently being investigated, the combination of aRCC1/2 with PD-L1 status exhibited the greatest potential as a predictive biomarker for patient selection, which was confirmed in both cohorts. The prognostic potential of the aRCC1/2 subdivision was evaluated in 476 clear cell RCC from TCGA. Here, aRCC2 was associated with significantly worse overall survival and cancer-specific survival in both univariate and multivariable analyses, accounting for age, sex, and clinicopathological parameters (TNM). In summary, categorization into aRCC1/2 proved to be a new risk stratification of aRCC which, in combination with PD-L1 status, enabled the retrospective identification of responders who benefited from combined therapy with ICI relative to sunitinib monotherapy. The analysis of IMmotion151 trial data utilized data generated by Genentech/Genentech Research and Early Development. Citation Format: Florian A. Büttner, Viktor Grünwald, Elfriede Noessner, Igor Tsaur, Jens Bedke, Matthias Schwab, Elke Schaeffeler. A PD-L1-independent phenotype uncovers responders to combined therapy with immune checkpoint inhibitors in kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7155.