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Abstract
Background There is an unmet need for predictive biomarkers for immune check point inhibitors (ICI) in ccRCC. We previously showed that tumor PD-L1 expression and serum KIM-1 levels were independently associated with treatment effect in adjuvant Nivolumab plus Ipilimumab (NIVO+IPI) vs placebo in localized ccRCC in Part A of Checkmate 914 (CM-914). Here we further investigated the role of PD-L1 and KIM-1 for association with response to NIVO+IPI in Part B of CM-914. In addition, we explored a novel human-interpretable image feature-(IF) based platform for biomarker identification.
Methods Patients enrolled in CM-914 Part B (n=825) with localized ccRCC were randomized post nephrectomy (Nx) to receive NIVO+IPI, NIVO or placebo as previously described.1 We used pre-treatment tumor Nx samples to assess PD-L1% tumor cell expression (%TC) using a PD-L1 IHC 28-8 pharm Dx assay. Assessment of KIM-1 levels was performed using Meso Scale Discovery (MSD) immunoassay using serum samples (n=704) collected prior to adjuvant dosing on Cycle 1 Day 1 (C1D1). IFs (n=1043) were used to predict clinically relevant cell types (macrophages, neutrophils, lymphocytes, and endothelial cells) and molecular phenotypes from histopathology H&E whole-slide images. The association between biomarkers and clinical outcomes (DFS and OS) was investigated by Kaplan-Meier (KM) and Cox proportional hazards analysis.
Results Patients with tumor PD-L1 expression level > 1% had improved DFS post treatment with NIVO+IPI versus placebo (HR=0.171 (0.036-0.823). When examining quartiles of KIM-1 levels, subjects with highest quartile levels baseline KIM-1 had worse clinical outcomes in placebo but not NIVO+IPI. In the IF analyses, subjects with PD-L1>=1% had higher levels of macrophages, neutrophils, and lymphocytes, while levels of endothelial cells were higher in subjects with PD-L1<1%. Subjects with higher levels of fibroblasts and lower levels of endothelial cells in tumor microenvironment (TME) had shorter DFS with NIVO+IPI.
Conclusions In the adjuvant setting, PD-L1 expression >=1% in tumor is potentially predictive of favorable NIVO+IPI outcome and elevated circulating KIM-1 levels are prognostic of worse clinical outcomes. Association of specific cell types, identified by IF provides initial characterization of TME responsive to NIVO+IPI treatment in patients with ccRCC.
Trial Registration NCT03138512.
Reference
Motzer RJ, et al. Journal of Clinical Oncology 2024.
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