抗体偶联药物联合免疫治疗尿路上皮癌的最新进展。
完整摘要 · 中文译文
尿路上皮癌（UC）仍是泌尿系统的主要恶性肿瘤，其治疗选择受限于铂类不耐受、原发或获得性耐药以及治疗相关毒性。抗体-药物偶联物（ADC）能够实现高活性细胞毒药物的肿瘤靶向递送，并已在晚期UC中显示出显著活性。ADC与免疫检查点抑制剂（ICI）的联合已从实验性治疗转变为成熟的临床实践，最突出的是恩沃利单抗（EV）联合帕博利珠单抗，以及在中国HER2表达性疾病中维迪西妥单抗（RC48）联合特瑞普利单抗。围手术期证据也已成熟，III期试验显示EV联合帕博利珠单抗在顺铂不耐受和顺铂耐受的肌层浸润性膀胱癌中均对无事件生存期和总生存期产生具有临床意义的改善。本综述整合了ADC-ICI联合治疗在不同疾病阶段的临床证据，讨论其机制依据、方案特异性安全性、生物标志物开发、耐药机制以及新兴的下一代ADC平台。我们区分临床前或机制性证据与临床疗效，并强调药理学协同作用尚未通过间接交叉试验比较得以确立。尽管若干生物标志物在生物学上具有合理性，但尚无任何标志物被前瞻性验证为ADC-ICI联合治疗获益的特异性预测因子。我们还讨论了围手术期和保膀胱应用，并确定了治疗序贯、毒性 监测以及生物标志物引导的溃疡性结肠炎（UC）精准治疗。
完整摘要 · 英文原文
Urothelial carcinoma (UC) remains a major malignancy of the urinary tract, with treatment options limited by platinum ineligibility, primary or acquired resistance, and treatment-related toxicity. Antibody-drug conjugates (ADCs) enable tumor-targeted delivery of highly potent cytotoxic agents and have demonstrated substantial activity in advanced UC. The combination of ADCs with immune checkpoint inhibitors (ICIs) has transitioned from experimental therapy to established clinical practice, most notably with enfortumab vedotin (EV) plus pembrolizumab and, in HER2-expressing disease in China, disitamab vedotin (RC48) plus toripalimab. Perioperative evidence has also matured, with phase III trials showing clinically meaningful improvements in event-free and overall survival for EV plus pembrolizumab in both cisplatin-ineligible and cisplatin-eligible muscle-invasive bladder cancer. This review integrates clinical evidence for ADC-ICI combinations across disease stages, discussing their mechanistic rationale, regimen-specific safety, biomarker development, resistance mechanisms, and emerging next-generation ADC platforms. We distinguish preclinical or mechanistic evidence from clinical efficacy and emphasize that pharmacologic synergy has not been established through indirect cross-trial comparisons. Although several biomarkers are biologically plausible, none have yet been prospectively validated as specific predictors of benefit from ADC-ICI combinations. We also discuss perioperative and bladder-sparing applications and identify priorities for treatment sequencing, toxicity surveillance, and biomarker-guided precision therapy in UC.