编者按：2026年美国临床肿瘤学会泌尿生殖系统肿瘤研讨会（ASCO GU 2026）已成功举行，作为泌尿生殖系统肿瘤领域的顶级学术盛会之一，大会发布的多项重磅研究深刻推动着全球临床诊疗格局的更迭。会议期间，肿瘤瞭望-泌尿时讯特邀海法瑞本医院Avivit Peer教授聚焦晚期尿路上皮癌（UC）的临床治疗热点与前沿探索，结合其团队发布的Keymaker-U04B研究数据进行深度解读。

Avivit Peer教授：今年的ASCO GU大会带来了非常多令人振奋的进展，其中我们深刻认识到，维恩妥尤单抗（EV）联合帕博利珠单抗方案，无论是对局限性疾病还是晚期转移性疾病的患者，都具备里程碑式的意义，堪称尿路上皮癌治疗领域的“圣杯”。

 

该联合方案的意义深远，正在改变我们的临床实践。无论是转移性疾病，还是局限性疾病的治疗布局，都因此发生了根本性的变化。我们已经正式进入了EV-Pembro方案在尿路上皮癌全人群中广泛应用的时代，这无疑是泌尿肿瘤领域无比激动人心的时刻。该方案为晚期尿路上皮癌患者带来了全新的治疗希望，不仅显著延长了患者的总生存期，更有效提升了患者的生存质量，从根本上改写了晚期尿路上皮癌既往的治疗格局。

 

Oncology Frontier:Targeted-immunotherapy combinations have dramatically changed survival outcomes for patients with advanced urothelial carcinoma.How do you view the clinical value of this therapeutic strategy?

 

Prof.Avivit Peer:We have seen many exciting advances at this year’s ASCO GU meeting.Among them，we strongly recognize that enfortumab vedotin(EV)plus pembrolizumab–the EV?Pembro regimen–represents a milestone for patients with both localized and advanced/metastatic disease，and can truly be called the“Holy Grail”in the treatment of urothelial carcinoma.

 

The results of this regimen are practice?changing and are fundamentally reshaping our clinical approach across both metastatic and localized disease settings.We have officially entered an era where EV?Pembro is broadly applicable across the full spectrum of urothelial carcinoma，marking an exciting time in genitourinary oncology.This regimen has brought new hope to patients with advanced disease，significantly prolonging overall survival while improving quality of life，and has fundamentally rewritten the previous treatment landscape of advanced urothelial carcinoma.

 

Avivit Peer教授：Keymaker-U04B研究的开展，源于我们临床中面临的真实痛点：EV-Pembro方案虽然疗效卓越，但并非所有患者都能从中获益。临床数据显示，大约10%的患者在接受该方案治疗后即出现原发性疾病进展，另有20%的患者仅能达到疾病稳定状态；即便在初期获得明确治疗响应的患者中，最终也有超过半数会出现疾病进展与获得性耐药。

 

基于这一现状，我们希望能针对肿瘤进展与耐药的核心机制，通过靶向治疗进一步提升疗效。我们探索了多种不同的策略，其中一个核心方向，就是进一步增强免疫检查点抑制剂的抗肿瘤效应。

 

在肿瘤的免疫逃逸机制中，LAG-3和TIGIT是目前领域内备受关注的两个核心靶点。LAG-3与PD-L1存在共表达，是肿瘤微环境中调节性T细胞耗竭的关键调控因子，而这种T细胞耗竭正是肿瘤发生耐药的重要机制之一。TIGIT则可在肿瘤细胞和抗原提呈细胞中表达，同样与T细胞耗竭、调节性T细胞的活性调控密切相关。

 

因此，靶向LAG-3和TIGIT的共表达进行干预，具备充分的理论合理性。前期的初步探索研究也显示，这一策略具备增强治疗响应的潜力，且不会带来过于严重的毒性反应。举个例子，既往我们在方案中添加伊匹木单抗（抗CTLA-4单抗）时，虽然可能增强疗效，但同时会显著增加治疗相关毒性；而靶向LAG-3和TIGIT，有望在仅适度增加治疗负担的前提下，提升治疗获益。

 

Keymaker?U04B是一项随机、开放标签、Ⅰ/Ⅱ期伞式子研究（NCT05845814），于2026 ASCO GU公布结果。该研究旨在探索在EV?Pembro一线标准方案基础上，联合LAG?3/TIGIT双靶点抑制剂能否进一步提升晚期尿路上皮癌疗效。但遗憾的是，Keymaker-U04B研究结果显示，在EV和帕博利珠单抗的基础上，分别联合针对LAG-3和TIGIT的双靶点制剂后，不仅显著升高了治疗相关毒性，导致更多患者因不良反应中断治疗，同时也未观察到患者临床疗效的显著提升。所以这是一项阴性结果的临床试验，它也给我们带来了明确的临床启示：对于晚期尿路上皮癌患者而言，当前治疗的“圣杯”依然是EV-Pembro方案，本次探索的三药联合策略，未能达到预期的疗效与安全性获益。

 

Oncology Frontier:You recently presented data from the Keymaker?U04B study at this congress.Could you describe the background of this study and the insights it provides for patients with advanced urothelial carcinoma?

 

Prof.Avivit Peer:The Keymaker?U04B study was designed to address a real clinical challenge:although EV?Pembro is highly effective，not all patients benefit.Clinical data show that approximately 10%of patients experience primary progression on this regimen，and another 20%achieve only stable disease.Even among patients who initially respond，more than half eventually progress and develop acquired resistance.

 

Against this background，we aimed to further improve efficacy by targeting core mechanisms of tumor progression and resistance.We explored multiple strategies，with a key focus on enhancing the anti?tumor activity of immune checkpoint inhibitors.

 

Among immune escape mechanisms，LAG?3 and TIGIT are two prominent targets.LAG?3 is frequently co?expressed with PD?L1 and is a key regulator of T?cell exhaustion in the tumor microenvironment，a major driver of resistance.TIGIT is expressed on tumor cells and antigen?presenting cells and is also closely linked to T?cell exhaustion and regulatory T?cell function.

 

Thus，targeting co?expression of LAG?3 and TIGIT is biologically rational.Preliminary studies suggested this approach could boost responses without excessive toxicity.For example，adding ipilimumab(anti?CTLA?4)may enhance efficacy but substantially increases treatment?related toxicity;targeting LAG?3 and TIGIT was expected to improve benefit with only a modest increase in therapeutic burden.

 

Keymaker?U04B(NCT05845814)is a randomized，open?label，PhaseⅠ/Ⅱumbrella trial whose results were presented at ASCO GU 2026.It investigated whether adding a dual LAG?3/TIGIT inhibitor to first?line EV?Pembro could further improve outcomes in advanced urothelial carcinoma.Unfortunately，the results were negative:adding either LAG?3 or TIGIT inhibitors to EV plus pembrolizumab significantly increased treatment?related toxicity，leading to more treatment discontinuations，without meaningful improvement in clinical efficacy.

 

This negative trial delivers a clear message:the“Holy Grail”for advanced urothelial carcinoma remains EV?Pembro，and the triplet combination strategy explored here did not achieve the expected benefit?risk profile.

 

Avivit Peer教授：我认为，一线EV-Pembro方案治疗进展后患者的治疗选择，是目前我们临床面临的核心难题，目前全球范围内还没有统一的标准治疗方案，但已经有多个明确的治疗方向可供临床选择。

 

首先，对于携带FGFR2/3融合或突变的患者，厄达替尼靶向治疗是非常重要的选择。同时，Memorial发表的一项研究数据显示，针对EV-Pembro方案治疗进展后的患者，接受含铂化疗可获得30%~40%的客观缓解率，疗效持续时间约4~5个月，因此含铂化疗也是临床中可行的后线治疗方案。

 

其次，HER2表达状态的检测至关重要，HER2将成为晚期尿路上皮癌后线治疗的核心靶点之一。对于HER2 IHC 3+过表达的患者，FDA已批准的德曲妥珠单抗（T-DXd）是非常合理的治疗选择，这款不同靶点、不同载药的ADC药物，为患者提供了全新的治疗路径。当然，目前全球还有多项临床试验正在开展，核心是评估不同靶点、不同载药的新型抗体药物偶联物（ADC），用于耐药后患者的治疗疗效，希望能对已经产生耐药的肿瘤细胞再次发挥杀伤作用。

 

总的来说，目前这类患者的治疗选择并不少。但我始终认为，对于患者而言，参加临床试验或许是目前最好的选择之一，这能为他们带来接触前沿治疗方案的机会，也有望带来新的治疗希望和更优的生存获益。

 

Oncology Frontier:Despite the remarkable efficacy of EV plus pembrolizumab，some patients do not respond or eventually progress.What subsequent treatment options are available for patients who progress on first?line therapy?

 

Prof.Avivit Peer:Management of patients progressing after first?line EV?Pembro is one of our most pressing clinical challenges.There is no universal standard of care globally，but several well?established options exist.

 

First，for patients with FGFR2/3 fusions or mutations，erdafitinib is a critically important targeted therapy.In addition，a study from Memorial Sloan Kettering demonstrated that platinum?based chemotherapy in patients post?EV?Pembro yields an objective response rate of 30%–40%，with a median duration of response of approximately 4–5 months，making it a valid later?line option.

 

Second，HER2 testing has become essential，as HER2 is emerging as a key target in later?line advanced urothelial carcinoma.For patients with HER2 IHC 3+overexpression，fam?trastuzumab deruxtecan(T?DXd)，approved by the FDA，is a rational choice.This distinct antibody?drug conjugate(ADC)with a different target and payload provides a novel therapeutic route.

 

Multiple ongoing clinical trials are evaluating novel ADCs with alternative targets and payloads for patients with resistant disease，with the goal of re?sensitizing tumors to treatment.

 

In summary，several therapeutic options are available.However，I continue to believe that participation in a clinical trial is among the best choices for these patients，offering access to innovative regimens and the potential for new hope and improved outcomes.

 

Avivit Peer教授

海法瑞本医院