BACKGROUND Immune checkpoint inhibitors (ICIs) are approved for first-line (cisplatin unfit, PD-L1+) and platinum-refractory urothelial carcinoma (UC). Still, most patients experience progressive disease (PD) as the best response. Although higher response rates to subsequent systemic treatment (SST) have been described, post-PD outcome data are scarce. OBJECTIVE To examine the outcome of UC patients who received SST and no SST after progressing to ICIs. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of UC patients progressing to frontline or later-line anti-PD-1/PD-L1 therapy in 10 European institutions was conducted between March 2013 and September 2017. INTERVENTION Post-PD management as per standard practice. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) was analyzed with a Kaplan-Meier model. Cox regression was used for multivariate analysis (MV). Impact of SST on OS was examined with a time-varying covariate model. RESULTS AND LIMITATIONS A total of 270 UC patients with PD to ICIs (69 frontline, 201 later line) were analyzed. Of the patients, 57% of frontline-ICI-PD and 34% of later-line-ICI-PD patients received SST, and SST had an impact on OS in MV (frontline: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.10-0.51, p <  0.001; later line: HR 0.22, 95% CI 0.13-0.36, p <  0.001). In the frontline-ICI-PD group, median OS with and without SST was 6.8 mo (95% CI 5.0-8.6) and 1.9 mo (95% CI 0.9-3.0), respectively. High disease burden (three or more metastatic sites: HR 2.49, p =  0.03; simultaneous liver/bone metastases: HR 3.93, p =  0.03) predicted worse survival. In later-line-ICI-PD group, response to ICIs (HR 0.37, p =  0.03), longer exposure to ICIs (HR 0.89, p =  0.002), and bone metastasis (HR 2.42, p <  0.001) predicted survival. The retrospective nature of this study and a lack of certain parameters limit the interpretation of our analysis. CONCLUSIONS Patients progressing to frontline ICIs are at risk of early death, excluding them from experiencing potential benefit from chemotherapy PATIENT SUMMARY: Our analysis suggests that outcomes after failing immunotherapy are poor, particularly in UC patients who received no prior chemotherapy.

中文翻译：

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进展为晚期尿路上皮癌的一线和二线抗PD-1 / PD-L1后的临床结局。

背景技术免疫检查点抑制剂（ICIs）被批准用于一线治疗（顺铂不适应症，PD-L1 +）和铂类难治性尿路上皮癌（UC）。尽管如此，大多数患者仍将进行性疾病（PD）视为最佳反应。尽管已描述了对后续全身治疗（SST）的更高应答率，但PD后的结局数据却很少。目的探讨UCI后接受SST而无SST的UC患者的结局。设计，地点和参与者对2013年3月至2017年9月间在10家欧洲机构中进行一线或后一线抗PD-1 / PD-L1治疗的UC患者进行了回顾性分析。实践。结果测量和统计分析使用Kaplan-Meier模型分析了总生存率（OS）。Cox回归用于多变量分析（MV）。使用时变协变量模型检查了SST对OS的影响。结果与局限性共分析了270例患有ICI的PD的UC UC患者（前线69位，后线201位）。在这些患者中，一线ICI-PD患者中有57％接受了SST，一线ICI-PD患者中有34％接受了SST，并且SST对MV的OS有影响（一线：危险比[HR] 0.22，95％置信区间[CI] 0.10-0.51，p <0.001；后一行：HR 0.22，95％CI 0.13-0.36，p <0.001）。在前线ICI-PD组中，有和没有SST的中位OS分别为6.8 mo（95％CI 5.0-8.6）和1.9 mo（95％CI 0.9-3.0）。较高的疾病负担（三个或更多转移部位：HR 2.49，p = 0.03；同时发生肝/骨转移：HR 3.93，p = 0.03）预示生存率较差。在后来的ICI-PD组中，对ICI的反应（HR 0.37，p = 0.03），更长的ICI暴露时间（HR 0.89，p = 0.002）和骨转移（HR 2.42，p <0.001）可预测存活率。这项研究的回顾性和缺乏某些参数限制了我们分析的解释。结论进展为一线ICI的患者有早期死亡的风险，使他们无法从化疗中获益。患者总结：我们的分析表明，免疫治疗失败后的预后较差，特别是在未接受过化疗的UC患者中。