Clinico-genomic characterization of patients with metastatic urothelial carcinoma in real-world practice and development of a novel bladder immune prognostic index (BIPI).
Authors: Szabados Bernadett , Ponz-Sarvise Mariano , Machado Robson , Saldana Diego , Kadel Edward Ernest , Banchereau Romain , Bouquet Fanny , Powles Thomas , Schroeder Carsten 
Published: February 2022

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Background: Real-world data (RWD) linking clinical outcomes with comprehensive genomic profiling (CGP) may enable identification of biomarkers to guide treatment selection and stratification in future trials. The primary objective was to characterize patients with metastatic urothelial carcinoma (mUC) included in a clinic-genomic database (CGDB), comprised of the electronic health record-derived Flatiron Health database with linked FoundationOne CGP results. As secondary objective, a novel Bladder Immune Prognostic Index (BIPI) was developed. Methods: A retrospective exploratory analysis was performed of de-identified RWD, retrieved from the CGDB. Data from mUC patients starting first-line single-agent immune checkpoint inhibitors (ICIs) and an unmatched group treated with front-line platinum-based chemotherapy (CHT) between Jan 1, 2011, and Sept 30, 2019, were analyzed and correlated with overall survival (OS). Known driver alterations, tumor mutational burden (TMB), and PD-L1 expression were described. A BIPI predicting outcome with ICIs was developed using a Cox-LASSO model and validated externally in a phase II trial (NCT02951767). Results: Of the 1021 patients with mUC identified in CGDB, 118 ICI-treated and 268 CHT-treated patients were included. Median follow-up duration was 9.4 and 14.5 months, respectively. Median OS was 5.4 months (95%CI, 3.3–9.2) with ICIs and 8.2 months (95%CI, 6.8–10.0) with CHT. In ICI-treated patients, low albumin and metastatic disease at initial presentation were associated with worse OS [HR (95%CI) 2.15 (1.18–3.90), p =.012; 2.58 (1.30–5.10), p =.007, respectively] whereas surgery for organ-confined disease and high TMB (≥10 mut/Mb) were associated with improved OS (HR (95%CI) 0.56 (0.36–0.88), p =.012; 0.58 [0.35–0.95]; p=.03), respectively. In CHT-treated patients, those with high APOBEC had worse OS (HR 1.43 [95% CI, 1.06–1.94]; p=.02). Neither PD-L1 (HR 0.96 [0.37-2.46]; p =.93), FGFR3 mutations (HR 0.98 [0.65-1.47]; p =.92) nor DNA damage-repair pathway alterations (HR 1.06 [0.73-1.52]; p =.77) were associated with OS. A novel BIPI for ICI-treated patients combining clinical and genomic variables (non-metastatic at initial diagnosis, normal albumin level, previous surgery for organ-confined disease, high TMB) was developed. Patients were categorized in 3 groups (low, intermediate, high risk) which correlated with OS. Median OS (95%CI) for low, intermediate and high risk was 11.7 (8.9−17.7), 4.1 (2.5–NE) and 2.4 months (1.0–4.0), (p <.001). Same results were observed in the validation cohort from an independent phase II immunotherapy trial in mUC (p <.001). Conclusions: This is the first time RWD including CGP were used to develop and validate a novel BIPI in mUC. This prognostic index may help patient selection in everyday practice and inform future trial design.