编者按：尿路上皮癌是泌尿系统常见的恶性肿瘤之一，其发病率及死亡率较高。尽管铂类化疗方案作为晚期尿路上皮癌的标准一线治疗具有一定疗效，但研究者对于更有效、更具个体化的治疗方案的探索从未停止。近年来，随着靶向治疗和免疫治疗领域的突破，各类联合方案的研究百花齐放，也为晚期尿路上皮癌患者带来了新的治疗希望。在刚刚结束的第39届欧洲泌尿外协会（EAU）大会中，《肿瘤瞭望》有幸在会议现场采访到了伦敦大学和巴茨癌症研究所Thomas Powles教授，他在采访中详细阐述了晚期尿路上皮癌领域的现状与挑战，以及未来值得探索的方向。

 

 

 

维迪西妥单抗已在HER2表达的局部晚期或转移性尿路上皮癌（LA/mUC）患者中显示良好的抗肿瘤活性和可控的安全性，无论是作为铂类经治后治疗的单药（HER2 IHC 3+/2+ORR：50.5%）还是与PD-1抑制剂联用（HER2 IHC 3+/2+ORR：83.3%；HER2 IHC 1+ORR：64.3%）。

 

DV-001是一项开放标签、随机、多中心、对照的Ⅲ期试验，旨在评估维迪西妥单抗+帕博利珠单抗对比化疗在既往未经治HER2表达LA/mUC患者中的疗效和安全性。研究的主要终点为无进展生存期（PFS）和总生存期（OS），次要终点包括客观缓解率（ORR）、缓解持续时间（DOR）、疾病控制率（DCR）、不良事件发生情况以及治疗对生活质量的影响等。目前该研究正在美国、加拿大和澳大利亚进行招募，并计划扩展至欧洲、拉丁美洲和亚洲的研究中心。

 

△研究设计

 

Thomas Powles教授：转移性尿路上皮癌的一线治疗格局确实发生了变化。在全球范围内，enfortumab vedotin和帕博利珠单抗的联合治疗效果显著优于铂类化疗（无论是否使用avelumab），总生存期延长一倍，无进展生存率减半，缓解率达到70%，其中完全缓解率达到30%。这使得enfortumab vedotin联合帕博利珠单抗成为新的标准治疗。对于那些无法接受这种联合疗法的患者，铂类化疗仍然是一种选择，而在世界许多地方，情况仍然如此。例如，在英国，我们还不能使用这种疗法。另外，需要重点关注的是关于不良事件和毒性管理的教育和培训。有意思的是，enfortumab vedotin和帕博利珠单抗的联合用药方案并不比化疗毒性更大；实际上，3级或4级不良事件发生率更低。不过，皮肤毒性和周围神经病变确实需要引起注意，因此有必要减少剂量和推迟治疗。此外，免疫疗法有时需要使用类固醇。这是尿路上皮癌治疗领域令人兴奋的时刻，这些进展改变了治疗模式。

 

Oncology Frontier:Currently，platinum-based combination chemotherapy is still the first-line standard treatment for advanced UC.What unmet needs do you think exist for patients with advanced UC?

 

Dr.Thomas Powles:The frontline treatment landscape in metastatic urothelial cancer has indeed changed.Globally，the combination of enfortumab vedotin and pembrolizumab significantly outperforms platinum-based chemotherapy，with or without avelumab，doubling the overall survival，halving the progression-free survival rate，and achieving response rates of 70%，including complete response rates of 30%.This makes enfortumab vedotin plus pembrolizumab the new standard of care.Platinum-based chemotherapy remains an option for those who don’t have access to this combination，which is still the case in many parts of the world.In the UK，for instance，we do not yet have access to it.Another focus should be on education and training regarding adverse events and toxicity management.Interestingly，the combination of enfortumab vedotin and pembrolizumab is not more toxic than chemotherapy;actually，the grade 3 or 4 adverse event rate was lower.However，skin toxicity and peripheral neuropathy do require attention，necessitating dose reductions and delays.Additionally，immune therapy sometimes necessitates the use of steroids.It’s an exciting time in urothelial cancer treatment，with these advances changing the treatment paradigm.

 

Thomas Powles教授：维迪西妥单抗是一种以单甲基澳瑞他汀E（MMAE）为有效载荷的HER2靶向抗体偶联药物（ADC），具备一定的潜力。中国学者在《临床肿瘤学杂志》（JCO）上发表的重要文章强调了它在HER2低表达和过表达情况下的活性。目前正在对HER2免疫组化（IHC）1、2或3+表达情况进行评估。该药已在中国获批作为单药治疗，目前正在探索与免疫检查点抑制剂的联合用药。这有可能与enfortumab vedotin联合帕博利珠单抗在特定患者中的疗效一致。与化疗对比的前线随机Ⅲ期试验至关重要，因为这种联合药物组合可能成为全球标准。与enfortumab vedotin+帕博利珠单抗的对比会是间接的，重点是疗效和潜在的不同毒性。

 

另一个关键问题是这些药物的排序，尤其是enfortumab vedotin+帕博利珠单抗新辅助治疗后的排序，特别是对复发患者而言。FDA最近批准了T-DXd（德曲妥珠单抗）用于HER2过表达实体瘤患者，这标志着该领域取得了快速进展。我们还需要考虑厄达替尼在FGFR改变患者中作为三线选择的作用，确认其独特的毒性特征。

 

Oncology Frontier:Previous studies have shown that patients with advanced UC with HER2 overexpression may benefit from treatment with disitamab vedotin.This phase 3 study uses a combination immune strategy.What are your expectations for its results?

 

Dr.Thomas Powles:Disitamab vedotin，a HER2-targeting antibody-drug conjugate(ADC)with monomethyl auristatin E(MMAE)as the payload，shows promise.Significant publication from China in the Journal of Clinical Oncology(JCO)highlighted its activity in both low and high HER2 expression contexts.It’s under evaluation in HER2 one，two，or three-plus expressions on immunohistochemistry(IHC).The drug is approved in China as a single agent and is being explored in combination with immune checkpoint inhibitors.This could potentially align with the efficacy of enfortumab vedotin and pembrolizumab in selected patients.Frontline randomized phaseⅢtrials against chemotherapy are crucial，as this combination may become a global standard.The comparison to enfortumab vedotin plus pembrolizumab will be indirect，focusing on efficacy and potentially differing toxicity profiles.

 

Sequencing of these agents，especially post-neoadjuvant use of enfortumab vedotin plus pembrolizumab，is another critical question，particularly for patients who relapse.The FDA’s recent basket approval of T-DXd(trastuzumab deruxtecan)in HER2 high，3 plus patients signifies rapid advancements in this area.We also need to consider the role of erdafitinib in FGFR-altered patients as a third-line option，acknowledging its unique toxicity profile.

 

Thomas Powles教授：enfortumab vedotin联合帕博利珠单抗作为一线疗法的推出具有变革性意义，它有可能扩展至围术期领域，因此有必要重新定义那些接受过这种联合疗法的患者的一线治疗。我们正在研究ADC的联合方案，如enfortumab vedotin与戈沙妥珠单抗的组合，显示出70%的应答率。这可能会挑战目前的一线标准。即将开展的研究（如TROPiCS-04）将戈沙妥珠单抗与单药紫杉类药物化疗进行了比较，这对确定其全球实用性至关重要。化疗联合ADC的方案也在探索之中，如卡铂与T-DXd或戈沙妥珠单抗联用。此外，在膀胱切除术后患者中使用生物标志物，特别是ctDNA，为早期干预和潜在的更高治愈率提供了一条有希望的路径。在这种情况下，像阿替利珠单抗这样的试验至关重要。总体而言，这一领域正在迅速发展，重点是完善既往经治患者的治疗方法，并利用生物标志物进行个体化治疗。我认为我们越早行动，最终治愈的患者就越多。

 

Oncology Frontier:What other directions do you think are worth exploring in the field of late-stage UC?

 

Dr.Thomas Powles:The introduction of enfortumab vedotin plus pembrolizumab as a first-line treatment has been transformative，potentially extending into the perioperative space and necessitating a redefinition of first-line therapy for those pre-treated with this combination.We’re looking at combinations of antibody-drug conjugates(ADCs)，such as enfortumab vedotin with sacituzumab govitecan，showing a 70%response rate.This may challenge the current first-line standard.Upcoming studies，such as TROPiCS-04，comparing sacituzumab govitecan against single-agent taxane chemotherapy，are crucial for defining its global utility.Combining chemotherapy with ADCs，like carboplatin with T-DXd or sacituzumab govitecan，is also under exploration.Furthermore，the use of biomarkers，particularly ctDNA in patients post-cystectomy，offers a promising avenue for early intervention and potentially higher cure rates.Trials like the one with atezolizumab in this context are pivotal.Overall，the landscape is rapidly evolving，with a focus on refining treatments for pre-treated patients and leveraging biomarkers for personalized therapy.I think the early we go，in the end the more patients we cure.

 

▌参考文献：

 

Powles T，Grande E，Van Der Heijden M，et al.Phase 3 study of disitamab vedotin with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2(DV-001;trial in progress).EAU 24;abstract A0746.

 

Thomas Powles教授

伦敦大学

巴茨癌症研究所

Thomas Powles教授是伦敦大学泌尿肿瘤学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。

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。