Molecular subtyping and immune-gene signatures identify a subset of clinical T1 high-grade (cT1 HG) and cT2 bladder urothelial carcinoma (UC) as candidates for single-agent immune checkpoint inhibition (ICI)

Abstract

We aimed to determine whether a similar ICI-based approach could be used by considering selected cT1 HG and cT2 bladder UC as optimal candidates for single-agent ICI. Data from transurethral resection of the bladder tumor (TURBT) specimens from 2 studies was evaluated. The MOL cohort included 206 patients (pts) with HG cT1N0M0 (N=87) or cT2N0M0 (N=119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (N=102), was used as ICI-treated UC reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher® assay). Immune-signatures scores (ISS) and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of the outcomes in relation to the molecular signatures and ISS. In the MOL cohort, luminal tumors (LT) were less frequently upstaged at RC vs non-LT (p=0.02). However, organ-confined (OC; pT£2; N=75) LT and non-OC (NOC; pT³3; N=24) LT at RC had statistically similar ISS, assessed with immune190 (0.09 vs 0.09), IFN-a (0.003 vs 0.26), IFN-g (-0.19 vs -0.17) and inflammation score (-0.1 vs -0.1). The remaining OC (N=57) and NOC (N=49) tumors were classified as basal (26/25), luminal infiltrated (19/11), claudin-low (11/8) and neuroendocrine-like (NE-like; 1/5). Except for the NE-like cases, the remaining OC and NOC non-LT showed higher ISS, with particularly high-scores for the claudin-low tumors. Progression-free survival outcomes for LT vs non-LT were favorable, but non-significant (p=0.2). In the MOL cohort, overall survival was inferior for Immune190-high vs low tumors (median split, p=0.042). In further analyzing the MOL cohort we identified a population of cT1-T2N0M0 tumors which shared molecular features with tumors included in PURE-01. These profiles were consistent regardless of whether the tumor was ultimately identified as OC or NOC, suggesting that treatment with ICI could be proposed to more selected cT1 HG. Clinical trials will be required to confirm the clinical utility of these observations.