658MO Cisplatin (cis)-related immunomodulation and efficacy with atezolizumab (atezo) + cis- vs carboplatin (carbo)-based chemotherapy (chemo) in metastatic urothelial cancer (mUC)

Abstract

Cis- but not carbo-based chemo leads to durable disease control in a subset of pts with mUC, but the underlying mechanisms remain elusive. Exploratory data from the randomised Ph III IMvigor130 study suggested improved OS with the addition of atezo to cis- but not carbo-based chemo (Galsky AACR 2021). Here we tested the hypothesis that cis may induce immunomodulatory effects. Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) obtained at Cycle (C) 1 Day (D) 1 and C3D1 from 70 IMvigor130 pts receiving atezo + platinum and gemcitabine (plt [cis or carbo]/gem; Arm A) or placebo + plt/gem (Arm C). Gene expression profiling of paired pre-/post- neoadjuvant gem + cis samples was used to study cis-related changes in the tumour microenvironment (TME; n=113). The impact of pre-treatment tumour PD-L1 immune cell expression on OS with cis vs carbo in Arms A and C is shown (Table). In IMvigor130 Arm C cis- vs carbo-treated pts, on-treatment enrichment of Hallmark TNFα signalling via NFKB and inflammatory response gene sets was observed across all immune cell clusters; trends were even more pronounced in Arm A. Among top-ranked genes enriched in PBMCs post-cis vs -carbo was NINJ1, which mediates plasma membrane rupture during lytic cell death, releasing damage-associated molecular patterns (eg, HMGB1). In a separate cohort in the neoadjuvant setting, TNFα signalling via NFKB was also enriched in paired tumour samples post- vs pre-gem + cis chemo.Table: 658MOIMvigor130: treatment subgroupsIC0/1IC2/3HR (95% CI)nMedian OS, monMedian OS, moArm A (atezo + cis/gem)10219.535Not reached0.46 (0.25, 0.83)Arm A (atezo + carbo/gem)24113.97316.60.85 (0.61, 1.17)Arm C (placebo + cis/gem)10212.83427.90.51 (0.30, 0.86)Arm C (placebo + carbo/gem)20713.05714.01.00 (0.71, 1.42)PD-L1 expression on tumour-infiltrating immune cells assessed from archival pre-treatment tumour samples (VENTANA SP142 assay). CI, confidence interval; HR, hazard ratio; IC0/1, presence of programmed death-ligand 1 (PD-L1)–expressing immune cells on <5% of the tumour area; IC2/3, presence of PD-L1–expressing immune cells on ≥5% of the tumour area; OS, overall survival. Open table in a new tab PD-L1 expression on tumour-infiltrating immune cells assessed from archival pre-treatment tumour samples (VENTANA SP142 assay). CI, confidence interval; HR, hazard ratio; IC0/1, presence of programmed death-ligand 1 (PD-L1)–expressing immune cells on <5% of the tumour area; IC2/3, presence of PD-L1–expressing immune cells on ≥5% of the tumour area; OS, overall survival. PD-L1 IC 2/3 status is associated with longer OS in cis- but not carbo-treated pts with mUC. Cis, vs carbo, is associated with increased TNFα-mediated proinflammatory signalling in circulating immune cells and the TME. Together these data suggest that cis/gem induces immunogenic cell death and enhances antitumour immunity, particularly when combined with atezo.