编者按：2026年ASCO GU如期启幕，作为全球泌尿肿瘤领域最具权威性与影响力的学术盛会，始终引领着尿路上皮癌、前列腺癌、肾癌等疾病诊疗的发展方向，而尿路上皮癌的精准靶向治疗，无疑是本届大会备受瞩目的核心焦点。随着抗体偶联药物（ADC）的研发突破与临床落地，人表皮生长因子受体2（HER2）这一经典靶点，正彻底改写尿路上皮癌的全球诊疗格局。肿瘤瞭望-泌尿时讯特邀伦敦大学、巴茨癌症研究所Thomas Powles教授，分享HER2靶点诊疗价值、检测规范，及中国创新药物维迪西妥单抗等的全球影响力。

 

Thomas Powles教授：HER2作为尿路上皮癌的生物标志物，其临床价值正日益凸显，核心原因是靶向HER2的ADC已成功应用于该疾病的临床治疗，如维迪西妥单抗、T-DXd等代表性药物。临床数据显示，约80%的尿路上皮癌患者存在不同程度的HER2表达，涵盖免疫组化（IHC）3+、2+及1+表达人群。

 

维迪西妥单抗作为靶向HER2的ADC药物，在HER2表达的尿路上皮癌患者中展现出优异的抗肿瘤活性：中国临床数据显示RC48单药治疗的C005&C009研究的客观缓解率是50.5%。更值得关注的是，由中国学者开展的维迪西妥单抗联合特瑞普利单抗治疗HER2表达晚期尿路上皮癌的随机Ⅲ期临床研究（RC48-C016）取得了突破性结果，该研究也是全球首个抗HER2-ADC用于晚期尿路上皮癌的随机对照Ⅲ期临床试验，结果证实这一联合方案在HER2生物标志物驱动的患者群体中存在显著的疗效叠加效应，其抗肿瘤疗效显著优于传统含铂化疗方案，研究结果同步发表于《新英格兰医学杂志》，具有里程碑式意义。

 

Oncology Frontier:What is your view on the diagnostic and therapeutic value of human epidermal growth factor receptor 2(HER2)in patients with urothelial carcinoma?

 

Professor Powles:The clinical value of HER2 as a biomarker in urothelial carcinoma is growing increasingly prominent，largely driven by the successful clinical application of HER2-targeted antibody-drug conjugates(ADCs)，most notably disitamab vedotin and trastuzumab deruxtecan(T-DXd).Clinical data indicate that approximately 80%of patients with urothelial carcinoma exhibit HER2 expression of varying degrees，including those with strongly positive immunohistochemistry(IHC)3+status，as well as IHC 2+and 1+expression.

 

As a HER2-targeted ADC，disitamab vedotin has demonstrated robust anti-tumor activity in patients with HER2-expressing urothelial carcinoma:Clinical data from China show an objective response rate(ORR)of 50.5%with RC48 single-agent treatment in the C005 and C009 studies.Of greater note，the randomized phase 3 clinical trial RC48-C016，conducted by Chinese investigators to evaluate disitamab vedotin plus toripalimab for HER2-expressing advanced urothelial carcinoma，has yielded groundbreaking results.As the world’s first randomized controlled phase 3 trial of a HER2-targeted ADC in advanced urothelial carcinoma，it confirmed a significant synergistic anti-tumor effect of this combination in the HER2 biomarker-driven population，with efficacy significantly superior to conventional platinum-based chemotherapy.The findings，concurrently published in*The New England Journal of Medicine*，carry landmark significance in the field.

 

Thomas Powles教授：目前关于HER2的检测方法及临床解读仍存在一定争议。传统的HER2阳性定义为IHC 3+或原位杂交阳性，该类人群仅占膀胱癌患者的20%左右，这一定义最初是为靶向治疗设计，并非适配ADC药物的临床应用。

 

随着ADC药物的临床应用，HER2低表达人群（IHC 1+、IHC 2+/ISH-）的临床价值被重新定义，维迪西妥单抗可用于所有HER2表达（IHC 1+、2+、3+）的尿路上皮癌患者，这一适用人群覆盖了绝大多数尿路上皮癌患者。临床数据显示，维迪西妥单抗在HER2传统阳性人群与低表达人群中的疗效无明显差异，未观察到显著的疗效富集现象。因此，相较于对HER2阳性进行精细化定义，通过免疫组化检测患者肿瘤是否存在HER2表达才是临床核心：若HER2检测为阴性，患者接受维迪西妥单抗治疗的缓解率显著偏低；若为阳性，无论属于传统阳性还是低表达亚组，维迪西妥单抗的缓解率基本一致，无需进一步区分亚组。

 

△维迪西妥单抗的国际性RC48-G001研究的主要终点ORR分析

 

△RC48-G001研究的cORR亚组分析

 

Oncology Frontier:Some studies have stratified HER2 expression into overexpression and low-expression subgroups.In clinical practice，how should HER2 expression levels be accurately assessed to guide treatment selection?

 

Professor Powles:There remains ongoing debate regarding the optimal methods for HER2 testing and their clinical interpretation.The traditional definition of HER2 positivity—IHC 3+or positive in situ hybridization(ISH)—applies to only around 20%of patients with bladder cancer.This definition was originally developed for targeted therapies，not for the clinical use of ADCs.

 

With the widespread clinical adoption of ADCs，the clinical value of patients with low HER2 expression(IHC 1+、IHC 2+/ISH-)has been redefined.Disitamab vedotin can be used in all patients with HER2-expressing urothelial carcinoma(IHC 1+，2+，or 3+)，an eligible population that covers the vast majority of patients with this disease.Clinical data show no significant difference in the efficacy of disitamab vedotin between patients with traditionally defined HER2 positivity and those with low HER2 expression，with no notable enrichment of treatment effect observed.

 

Therefore，rather than refining the definition of HER2 positivity，the core clinical priority is to detect the presence or absence of any HER2 expression in the patient’s tumor via IHC.Patients with negative HER2 testing have a significantly lower response rate to disitamab vedotin;for those with positive HER2 expression，response rates to disitamab vedotin are largely consistent regardless of whether they fall into the traditionally positive or low-expression subgroups，with no need for further stratification.

 

Thomas Powles教授：以维迪西妥单抗为代表的中国创新药物，已对全球尿路上皮癌的临床实践产生了颠覆性影响。维迪西妥单抗单药及联合特瑞普利单抗的核心临床数据均来自中国研究，其中郭军教授团队开展的Ⅲ期研究成果发表于《新英格兰医学杂志》，充分证实了该方案的临床价值，目前这一方案已显著改变中国尿路上皮癌的临床治疗实践。

 

从全球视角来看，维恩妥尤单抗联合帕博利珠单抗是目前临床应用较广泛的治疗方案，其循证医学证据主要来自EV-302、EV-303、EV-304等全球多中心研究，其中EV-303研究证实该联合方案可显著改善不适合顺铂治疗的肌层浸润性膀胱癌患者的病理缓解率及无病生存期。对比来看，维恩妥尤单抗方案并非生物标志物驱动，而维迪西妥单抗方案以HER2表达为核心生物标志物，但两者的临床活性相似，疗效的共性远大于差异。随着维迪西妥单抗联合帕博利珠单抗的全球随机试验开展，若取得阳性结果，将为全球尿路上皮癌患者提供新的治疗选择，未来治疗方案的选择或更多由临床医生的诊疗偏好决定。目前临床实践中，HER2过表达的尿路上皮癌患者在中国多接受维迪西妥单抗联合特瑞普利单抗治疗，而全球其他地区仍以维恩妥尤单抗联合帕博利珠单抗的全人群治疗为主。

 

中国创新的ADC药物对全球尿路上皮癌治疗格局的影响远不止于维迪西妥单抗：中国药企已快速研发出多款新型ADC药物，如搭载拓扑异构酶1（Topo1）载荷的HER3、HER1 ADC，以及芦康沙妥珠单抗（sac-TMT）等，这类药物正以爆发式态势进入全球市场。这一趋势不仅深刻影响了全球尿路上皮癌的临床试验设计与开展，更将为全球患者带来切实的临床获益。此外，中国的肿瘤药物研发已从最初的中国专属临床试验，逐步发展为参与并主导全球多中心研究，中国正深度融入全球肿瘤药物研发的国际体系，在全球肿瘤药物的研发决策与临床应用中占据了主导地位。

 

Oncology Frontier:Based on relevant study data，what is your view on the impact of Chinese innovative drugs on the global treatment landscape of urothelial carcinoma?

 

Professor Powles:Chinese innovative agents，led by disitamab vedotin，have already had a transformative impact on the global clinical practice of urothelial carcinoma.The core clinical data for disitamab vedotin，both as monotherapy and in combination with toripalimab，come from Chinese studies.Among them，the phase 3 trial conducted by Professor Jun Guo’s team，whose findings were published in*The New England Journal of Medicine*，fully validated the clinical value of this regimen，which has now dramatically reshaped routine clinical practice for urothelial carcinoma in China.

 

From a global perspective，the combination of enfortumab vedotin(EV)plus pembrolizumab is currently the most widely used regimen in clinical practice，with evidence-based data primarily from global multicenter trials including EV-302，EV-303，and EV-304.Of these，the EV-303 trial confirmed that this combination significantly improves pathological response rates and disease-free survival(DFS)in patients with cisplatin-ineligible muscle-invasive bladder cancer.In comparison，the EV-based regimen is not biomarker-driven，while the disitamab vedotin-based regimen centers on HER2 expression as its core biomarker.Despite this difference，the two regimens have similar clinical activity，with far more commonalities than differences in their efficacy.With the ongoing global randomized trial of disitamab vedotin plus pembrolizumab，positive results will provide a new treatment option for patients with urothelial carcinoma worldwide，and treatment selection may in the future be driven more by clinicians’practice preferences.In current clinical practice，patients with HER2-overexpressing urothelial carcinoma in China are mostly treated with disitamab vedotin plus toripalimab，while the all-comer regimen of enfortumab vedotin plus pembrolizumab remains the mainstay in other regions of the world.

 

The impact of innovative Chinese ADCs on the global urothelial carcinoma treatment landscape extends far beyond disitamab vedotin.Chinese pharmaceutical companies have rapidly developed a number of novel ADCs，including HER3-and HER1-targeted ADCs with topoisomerase 1(Topo1)payloads，as well as sacituzumab govitecan(sac-TMT)，among others.These agents are entering the global market at an explosive pace.This trend is not only profoundly reshaping the design and conduct of global clinical trials in urothelial carcinoma，but will also deliver tangible clinical benefits to patients worldwide.

 

In addition，China’s oncology drug R&D has evolved from initially conducting China-only clinical trials to increasingly participating in and leading global multicenter studies.China is now deeply integrated into the global oncology drug R&D ecosystem，and has taken a leading role in decision-making for global oncology drug development and clinical application.