PURPOSE This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record-derived real-world data (RWD) combined with FoundationOne comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune performance index (BIPI). EXPERIMENTAL DESIGN Patients with mUC who started front-line single-agent immune checkpoint inhibitors (ICI) and an unmatched group treated with front-line platinum-based chemotherapy between January 1, 2011, and September 30, 2019, were selected. Clinical and genomic data were correlated with overall survival (OS). A novel BIPI predicting outcome with ICIs was developed using machine learning methods and validated using data from a phase II trial (NCT02951767). RESULTS In ICI-treated patients (n = 118), high tumor mutational burden (≥10 mutations/megabase) was associated with improved OS (HR, 0.58; 95% CI, 0.35-0.95; P = 0.03). In chemotherapy-treated patients (n = 268), those with high APOBEC mutational signature had worse OS (HR, 1.43; 95% CI, 1.06-1.94; P = 0.02). Neither FGFR3 mutations nor DNA damage-repair pathway alterations were associated with OS. A novel BIPI combining clinical and genomic variables (nonmetastatic at initial diagnosis, normal or above normal albumin level at baseline, prior surgery for organ-confined disease, high tumor mutational burden) identified ICI-treated patients with longest OS and was validated in an independent dataset. CONCLUSIONS Contemporary RWD including FoundationOne CGP can be used to characterize outcomes in real-world patients according to biomarkers beyond PD-L1. A validated, novel clinico-genomic BIPI demonstrated satisfactory prognostic performance for OS in patients with mUC receiving front-line ICI therapy.

中文翻译：

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现实世界实践中转移性尿路上皮癌患者的临床基因组特征确定了一种新的膀胱免疫性能指数 (BIPI)。

目的 这项对现有最大临床基因组数据库的回顾性分析使用去识别的患者级电子健康记录衍生的真实世界数据 (RWD) 结合 FoundationOne 综合基因组分析 (CGP) 来表征转移性尿路上皮癌 (mUC) 患者在现实环境中进行治疗，检测潜在的生物标志物，并制定膀胱免疫性能指数 (BIPI)。实验设计 选择在 2011 年 1 月 1 日至 2019 年 9 月 30 日期间开始一线单药免疫检查点抑制剂 (ICI) 的 mUC 患者和接受一线含铂化疗治疗的无与伦比的组。临床和基因组数据与总生存期 (OS) 相关。使用机器学习方法开发了一种新的 ICI BIPI 预测结果，并使用来自 II 期试验 (NCT02951767) 的数据进行了验证。结果 在接受 ICI 治疗的患者（n = 118）中，高肿瘤突变负荷（≥10 个突变/兆碱基）与 OS 改善相关（HR，0.58；95% CI，0.35-0.95；P = 0.03）。在接受化疗的患者（n = 268）中，具有高 APOBEC 突变特征的患者 OS 较差（HR，1.43；95% CI，1.06-1.94；P = 0.02）。FGFR3 突变和 DNA 损伤修复途径的改变都与 OS 无关。一种新的 BIPI 结合了临床和基因组变量（初始诊断时非转移性、基线时白蛋白水平正常或高于正常水平、器官局限疾病的先前手术、高肿瘤突变负担）确定了 ICI 治疗的患者具有最长的 OS，并在独立的数据集。结论 包括 FoundationOne CGP 在内的当代 RWD 可用于根据 PD-L1 以外的生物标志物来表征现实世界患者的结果。一种经过验证的新型临床基因组 BIPI 在接受一线 ICI 治疗的 mUC 患者中显示出令人满意的 OS 预后表现。