编者按：抗体偶联药物（ADC）与免疫检查点抑制剂的联合策略，正在迅速改写尿路上皮癌的临床实践；与此同时，循环肿瘤DNA（ctDNA）作为一种极具前景的生物标志物，为实现精准医疗与“保膀胱”治疗策略提供了关键依据。在近期举行的第十五届上海泌尿肿瘤学术大会上，肿瘤瞭望-泌尿时讯特邀Thomas Powles教授，围绕围手术期治疗策略的优化、生物标志物的筛选价值，以及未来膀胱癌治疗中“去手术化”趋势展开深入探讨。

 

Thomas Powles教授：这是当前尿路上皮癌领域最具挑战性且备受关注的问题。事实上，在晚期转移性尿路上皮癌患者中，我们已经观察到治疗格局的革命性变化；以维恩妥尤单抗联合帕博利珠单抗（EVP）、维迪西妥单抗联合特瑞普利单抗为代表的ADC联合免疫方案，已在转移阶段展现出优于传统化疗的潜力。临床数据显示，从总生存期（OS）来看，EVP联合方案的疗效近乎是传统化疗的两倍。

 

肌层浸润性膀胱癌（MIBC）围手术期治疗同样取得了突破。在MIBC的新辅助治疗中，EV联合帕博利珠单抗方案取得了约55%的病理完全缓解（pCR）率，其疗效提示其可能优于单纯膀胱根治性切除术。此外，NIAGARA研究评估了度伐利尤单抗联合新辅助化疗（顺铂+吉西他滨）的疗效。结果显示，联合方案可使患者的死亡风险降低25%，进一步证实了早期免疫干预在改善预后中的关键作用。

 

综合现有证据，未来无论联合ADC还是铂类化疗，早期引入免疫治疗均能显著改善患者预后；其次，随着EV联合帕博利珠单抗等方案在新辅助治疗中卓越数据的积累，ADC联合免疫有望在未来取代新辅助化疗，成为MIBC围手术期的标准治疗模式。

 

Professor Thomas Powles:This is currently the most challenging and high-profile question in the field of urothelial carcinoma.In fact，we have already observed a fundamental paradigm shift in advanced metastatic disease.

 

Progress in Metastatic Disease:ADC+ICI combinations—represented by Enfortumab Vedotin(EV)plus Pembrolizumab et al.—have demonstrated superior potential over traditional chemotherapy in the metastatic stage.Clinical data indicate that these novel combinations nearly double the overall survival(OS)compared to conventional chemotherapy.

 

Breakthroughs in Perioperative MIBC:In the neoadjuvant setting for muscle-invasive bladder cancer(MIBC)，the EV plus Pembrolizumab regimen achieved a pathologic complete response(pCR)rate of approximately 55%，suggesting efficacy that may surpass radical cystectomy alone.Additionally，the NIAGARA study evaluated Durvalumab combined with neoadjuvant chemotherapy(Cisplatin+Gemcitabine).Results showed a 25%reduction in the risk of death，further confirming the critical role of early immune intervention in improving prognosis.

 

Thomas Powles教授：随着治疗手段不断丰富，我们必须审慎思考：是否所有患者均需接受高强度全身治疗？是否存在部分人群可避免此类干预？目前，我们仍缺乏理想的预测标志物。PD-L1表达、肿瘤突变负荷（TMB）及T细胞效应标签等组织学标志物，均未能稳定可靠地预测免疫治疗疗效。在ADC治疗中，Nectin-4的表达水平亦未显示与ICI疗效存在明确相关性。

 

尽管传统标志物存在局限性，但ctDNA作为新兴标志物展现出重要潜力——它可精准识别高进展风险人群，而风险状态直接决定患者预后。未来，我们有望迈入一个由ctDNA与尿液肿瘤DNA（utDNA）共同引导的个体化治疗时代。通过动态监测这些标志物，对于治疗后实现ctDNA清除的患者，或可考虑缩短疗程；甚至对ctDNA持续阴性者，可避免膀胱切除术。这种基于生物标志物的“减法策略”，将成为实现精准治疗、避免过度干预的关键。

 

Professor Thomas Powles:With an expanding armamentarium of treatments，we must critically consider:Do all patients require intensive systemic therapy?Are there populations who can safely forgo such interventions?

 

Currently，we still lack the"ideal"predictive biomarker.Histological markers such as PD-L1 expression，tumor mutational burden(TMB)，and T-cell effector signatures have not consistently or reliably predicted immunotherapy outcomes.In the context of ADC therapy，Nectin-4 expression has also failed to show a clear correlation with ICI efficacy.Despite the limitations of traditional markers，ctDNA has shown significant potential as an emerging biomarker.It can precisely identify populations at high risk of progression，which directly dictates prognosis.We are moving toward an era of individualized treatment guided by both ctDNA and urinary tumor DNA(utDNA).By dynamically monitoring these markers，we may consider shortening the duration of treatment for patients who achieve ctDNA clearance;for those who remain persistently ctDNA-negative，we may even be able to avoid cystectomy.This biomarker-driven"subtraction strategy"will be key to achieving precision medicine and avoiding over-intervention.

 

Thomas Powles教授：ctDNA正在深刻改变MIBC的治疗逻辑，推动临床从“一刀切”转向个体化模式。不同患者的风险差异显著，而ctDNA正是识别这一差异的重要工具。IMvigor011研究针对术后ctDNA阳性的MIBC患者，随机给予阿替利珠单抗或安慰剂，而对ctDNA阴性者仅进行观察。结果显示，ctDNA阴性患者预后较佳，两年内膀胱癌相关死亡率仅为约3%，提示辅助干预对其价值有限。相反，ctDNA阳性患者则能够从免疫治疗中明确获益。

 

在新辅助治疗中，ctDNA同样具备重要预测作用。研究显示，吉西他滨+顺铂联合度伐利尤单抗可使70%的患者实现ctDNA清除，而EV联合帕博利珠单抗方案的清除率预计更高。若患者在新辅助治疗后，结合MRI影像学检查未见疾病征象，且ctDNA为阴性，则提示其可能已达到cCR，局部复发风险极低。膀胱切除术对高龄患者（如70~80岁人群）负担较重。

 

展望未来，通过整合MRI、ctDNA与utDNA的多维度评估，并应用RC48联合特瑞普利单抗、EV联合帕博利珠单抗等高效方案，我们有望使超过50%的患者在无需手术的情况下获得临床治愈。

 

Professor Thomas Powles:ctDNA is profoundly altering the treatment logic for MIBC，pushing clinical practice from a"one-size-fits-all"approach toward an individualized model.Risk profiles vary significantly between patients，and ctDNA is a vital tool for identifying these differences.

 

Evidence from IMvigor011:This study focused on MIBC patients who were ctDNA-positive post-surgery，randomizing them to Atezolizumab or placebo，while ctDNA-negative patients were only observed.Results showed that ctDNA-negative patients had an excellent prognosis，with a two-year bladder cancer-related mortality rate of only about 3%，suggesting limited value for adjuvant intervention in this group.Conversely，ctDNA-positive patients derived a clear benefit from immunotherapy.

 

Predictive Value in the Neoadjuvant Phase:In the neoadjuvant setting，ctDNA also plays a predictive role.Research shows that Gemcitabine+Cisplatin plus Durvalumab can lead to ctDNA clearance in 70%of patients，with the EV+Pembrolizumab regimen expected to achieve even higher clearance rates.

 

Driving the Goal of"De-escalated Surgery":If a patient shows no evidence of disease on MRI and is ctDNA-negative following neoadjuvant therapy，it suggests a clinical complete response(cCR)with a very low risk of local recurrence.Radical cystectomy is a heavy burden，particularly for elderly patients(aged 70–80).Looking ahead，by integrating multi-dimensional assessments—including MRI，ctDNA，and utDNA—and applying highly effective regimens such as Disitamab Vedotin(RC48)plus Toripalimab or EV plus Pembrolizumab，we hope to enable over 50%of patients to achieve clinical cure without the need for surgery.

 

Thomas Powles教授

伦敦大学泌尿生殖系癌症教授、巴特癌症中心主任

Thomas Powles教授是伦敦大学泌尿生殖系统肿瘤教授和巴茨癌症研究所负责人。

他在泌尿系统癌症生物标志物和新药策略的开发方面发挥了重要作用，特别是肾细胞癌的一线免疫/靶向治疗组合、膀胱癌的免疫检查点抑制剂单独或联合用药等。

Thomas Powles教授领导了多项临床试验（包括21项随机试验）和转化肿瘤学研究项目，这些项目均刊登在主要期刊上。

Powles教授现任《肿瘤学年鉴》（Annals of Oncology）主编、ESMO理事会成员以及EAU肾癌指南的成员。

目前的工作重点是早期膀胱癌和肾癌的新型辅助/新辅助疗法，以及术后复发风险患者的识别。