编者按：以铂类为基础的化疗方案仍然是晚期尿路上皮癌（UC）治疗的基石，但仍未满足患者的长期生存需求；于法国巴黎举行的第39届欧洲泌尿外科协会年会（EAU24）聚焦了多项尿路上皮癌研究热点，来自斯图加特凯瑟琳医院（Klinikum Stuttgart Katharinen Hospital）的Jens Bedke教授在大会分享了EV-302/KEYNOTE-A39研究结果。《肿瘤瞭望-泌尿时讯》特邀该领域知名专家Jens Bedke教授分享免疫治疗现状、近期临床试验的重大进展，以及UC治疗未来方向等内容。

Jens Bedke教授：我认为膀胱癌（特别是转移性膀胱癌）患者未满足的临床需求是目前面临的一个重要问题。我们知道，随着患者年龄不断增长，转移性尿路上皮癌的发病率和总体负担在不断增加。而目前的主要治疗方法是铂类化疗，因为基于铂类的化疗方案有效率较高；但使用基于顺铂和卡铂的治疗方案，只有5%~10%的患者获得长期生存。即使我们在铂类化疗后维持治疗，使患者维持较高缓解率（甚至可能缓解程度更高），但在这种情况下的患者长期生存依然难以满足。这就引出了一个问题，未来我们应如何改进，并超越目前的铂类化疗策略。

 

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

 

Dr.Jens Bedke:Thanks a lot for inviting me.So，I think it’s a question of high importance:what are the unmet clinical needs in bladder cancer，especially metastatic bladder cancer?We know that patients are getting older，and the incidence and the general burden of metastatic urothelial cancer is increasing.And the mainstay for treatment is currently platinum-based chemotherapy.What we know about platinum-based chemotherapy is that it’s effective，but we only have long-term survivors on a 5 to 10%level with cisplatin and carboplatinum-based regimens.Even if we have maintenance regimens and concepts after the induction period of platinum-based chemotherapy，response rates are there but they could be higher，and especially，long-term survivors are still missing in this situation.This leads to the question:how can we improve and go beyond platinum-based chemotherapy for the future.

Jens Bedke教授：我们在转移性膀胱癌治疗中引入免疫检查点抑制剂已有5~6年时间。毫无疑问，免疫疗法（IO）相关药物确实改善了转移性膀胱癌患者的结局、总生存以及无进展生存率，无论是在铂类化疗后的患者，还是不符合铂类药物治疗标准而接受免疫检查点抑制剂（帕博利珠单抗或阿替利珠单抗等）单药治疗的患者，其中部分患者可能为PD-L1阳性。当然二线治疗中也有免疫检查点抑制剂的存在。我认为过去开发的治疗策略以化疗为主，随后出现了免疫检查点抑制剂，但也许仅作为单药使用。

 

现在EV-302的研究方案则是一种全新设计，将免疫检查点抑制剂（该研究使用了PD-1类型的帕博利珠单抗）与专门设计的抗体偶联药物维恩妥尤单抗（Enfortumab Vedotin）相结合。其中维恩妥尤单抗是一种Nectin-4靶向抗体（Nectin-4是一种表达在肿瘤细胞表面的蛋白），维恩妥尤单抗可将化疗药物MMAE传递给表达Nectin-4的细胞，由于维恩妥尤单抗不仅具有直接的细胞毒性，同时也有旁观者效应，从而引起肿瘤细胞死亡。在3期试验EV-302中将ADC与免疫检查点抑制剂结合起来，患者以三周为周期，接受维恩妥尤单抗联合帕博利珠单抗治疗。在第1天和第8天给予维恩妥尤单抗，并使用吉西他滨/顺铂或吉西他滨/卡铂作为比较药物进行化疗。试验结果表明，无进展生存期和总生存期的双重主要终点均已达到。

 

因此与铂类化疗相比，维恩妥尤单抗联合帕博利珠单抗的无进展生存期增加了一倍；在EV-302试验方案的PFS约为12个月，而铂类化疗为6个月。此外，总体生存率的第二个主要终点也已达到。在转移性膀胱癌的一线治疗中，帕博利珠单抗联合维恩妥尤单抗的中位总生存期为32个月。最后值得一提的是患者缓解率，维恩妥尤单抗联合帕博利珠单抗的缓解率为68%，其中30%的患者获得完全缓解。

 

本次EAU会议上的新内容是我们介绍了上尿路（输尿管、肾盂）和膀胱癌的最新情况。EV-302中27%的患者患有上尿路尿路上皮癌。亚组分析结果表明，PFS和OS结果以及缓解率与尿路上皮癌的所有队列一致。我认为这是一个非常重要的信号，因为通常上尿路（输尿管、肾盂）对铂类治疗的反应较低。在EAU会议上公布的EV-302结果表明，该方案治疗对于上尿路尿路上皮癌的疗效甚至和经典膀胱癌一样有效。

 

Urology Frontier：Immunotherapy for UC has progressed rapidly in recent years，and NEJM also announced the latest EV-302/KEYNOTE-A39 study results.What breakthroughs did this research achieve?

 

Dr.Jens Bedke:Well，if you look back，it’s like five to six years since we had the introduction of immune checkpoint inhibitors in the metastatic setting of bladder cancer.Without any doubt，the IO(immunotherapy)agents have definitely improved the outcomes，the survival rates，and also the progression-free survival rates in metastatic bladder cancer patients，either after the induction of platinum-based chemotherapy or if they are platinum-ineligible，or just if there’s a PD-L1 positive fraction of patients receiving checkpoint monotherapy with Pembrolizumab or Atezolizumab.And of course，in the second-line setting，the checkpoint inhibitors.And I think what we have developed over the past is that we have the mainstay of chemotherapy，then we had the addition of the immune checkpoint inhibitors，maybe just as a single agent.

 

And now，the approach of the EV-302 was a totally new design to combine the IO agents，here the PD-1 antibody Pembrolizumab，with specially designed chemotherapy from the antibody-drug conjugate Enfortumab Vedotin.So，Enfortumab Vedotin is a Nectin-4 targeting antibody，and Nectin-4 is a cell surface protein which is expressed on the cell surface of the tumor cells.And to this antibody，we have a chemotherapeutic agent which is called MMAE，and by the internalization of the Nectin-4 antibody then Enfortumab Vedotin，we have this direct cytotoxic activity of Enfortumab Vedotin，but we also have bystander effects and they have an immunogenic cell death which is provoked by Enfortumab Vedotin.And the rationale was to combine the ADC plus the checkpoint inhibitor in the phase 3 trial EV-302.So，what has been done in EV-302，it was a phase 3，1-to-1 randomized trial;patients received EV plus Pembrolizumab in three-week cycles.EV was given on day 1 and day 8，and they had the chemotherapy with Gemcitabine/Cisplatin or Gemcitabine/Carboplatin as a comparator.And the trial definitely had a positive outcome.The dual primary endpoints of progression-free survival and overall survival were significantly met.

 

EV-302 had two dual primary endpoints which were significantly met.So，the progression-free survival of EV plus Pembrolizumab compared to platinum-based chemotherapy was doubled;we had a PFS of around 12 months compared to six months with platinum-based chemotherapy in the EV-302 trial.And in addition，also the overall survival was significantly improved;the second dual primary endpoint，and they had a median overall survival of 32 months observed by EV plus Pembrolizumab in this first-line setting of metastatic bladder carcinoma.And last but not least，the response rate;they had a response rate of 68%with EV plus Pembrolizumab，and 30%of the patients had a complete response.

 

Now，what was new at this EAU meeting，we presented an update of the upper tract(ureter，renal pelvis)and bladder carcinoma.So，27%of the patients in EV-302 had an upper tract carcinoma.And what we observed for the PFS and OS as a subgroup analysis，that results for the PFS and OS，but also the response rates were in line with the all-comer cohort for the upper tract.I think this is a very important signal because usually，renal pelvis and ureter，so the upper tract urothelial carcinoma，have a lower response to platinum-based therapy.And this is，let’s say，a location of concern.And the results of EV-302 presented here at the EAU meeting demonstrate that it’s very active and as active as the classical bladder carcinoma.

 

Jens Bedke教授：一如既往，如果有新类别的药物出现，我们就会特别关注副作用。也许是新问题，而重要的是免疫检查点抑制剂可诱发皮炎。维恩妥尤单抗相关研究表明，皮炎问题值得关注，而皮肤反应是值得特别关注的不良事件。另一个特别令人感兴趣的是神经性疾病，感觉神经病或运动神经病，可能在维恩妥尤单抗联合帕博利珠单抗治疗时发生。

 

我们该如何处理呢？我认为首先是要意识到这些副作用，并且需要跨学科管理，这样也能通过这种组合治疗策略获得新的治疗经验。当然也可以减少这些药物的剂量，甚至中断剂量。我们需要尽早监测这些副作用，以便对其进行跟踪，并在副作用出现后及时对其进行管理。如果早期开始治疗不良事件，通常会取得较好的疗效。

 

Urology Frontier：Combined immunotherapy may increase adverse reactions.How do you think it should be managed in clinical practice?

 

Dr.Jens Bedke:Well，as always，if you have new classes of drugs，we have new side effects of special interest.And what is maybe new or what is of importance，we know that immune checkpoint inhibitors can induce dermatitis.We knew that from EV that dermatitis is of concern，and in the combination，skin reactions are adverse events of special interest.Another special interest is the neuropathy，the sensory or sometimes motor neuropathy which can develop under EV plus Pembrolizumab.How shall we manage that?I think first of all，it’s of importance to have awareness for these side effects and that you have an interdisciplinary management.So，especially if you gain new experience with this combination.So，what can you do?Well，of course，you have the possibility of dose reduction，dose modification，dose interruptions with these agents.Please have an early monitoring for these side effects so that they are tracked and the side effects once they develop are managed promptly.And if you start early treatment of the adverse events，then I think you will have success but they do not run away and aggravate.

 

Jens Bedke教授：目前确实存在转移性尿路上皮癌患者，那么应如何预防转移性疾病的发展？我认为目前围手术期、新辅助治疗方面取得了巨大进展，如维恩妥尤单抗联合帕博利珠单抗治疗策略抑或其他ADC组合的临床试验，以及本届EAU大会上CheckMate-274的最新进展。CheckMate-274是一项膀胱切除术后纳武利尤单抗辅助治疗的试验，我们在本届EAU大会上看到了该试验的总体生存数据。纳武利尤单抗在辅助方案中使用一年，但纳武利尤单抗治疗组与对照组或安慰剂治疗组之间的差异非常明显，而且差异随着时间的推移而增加。我认为在本次试验三或四年后，总体生存提高了10个月。因此可以选择患者尽早开始辅助治疗，并预防转移性疾病发展。另一方面，这个问题也与生物标志物有关。生物标志物的领域非常广泛，但我们在这里从IMvigor011试验中得到了有趣演示，该试验中患者接受了循环肿瘤DNA（ctDNA）检测；ctDNA结果阳性患者将被随机分配接受阿替利珠单抗辅助治疗或安慰剂治疗。大会上介绍了ctDNA阴性患者及其随访情况，非常有趣的是，如果患者ctDNA随着时间推移仍呈阴性状态，则膀胱切除术后的膀胱癌复发风险非常低；如果ctDNA从阴性转为阳性，那么复发风险就会存在并可能增加。

 

Urology Frontier：How should we identify the advantaged groups and thereby improve the clinical benefits for patients?

 

Dr.Jens Bedke:Well，I mean，with metastatic disease as present，it’s present.So，the question is，how can you prevent the development of metastatic disease?And I think that we have great development in the perioperative setting，new adjuvant treatment either in clinical trials with this combination of EV plus Pembrolizumab or other ADCs，or as we have observed here at the current EAU Congress，the latest update from the CheckMate-274 trial.This is an adjuvant trial of Nivolumab after cystectomy，and we have seen the overall survival data of this trial here at this EAU Congress.Nivolumab in the adjuvant scenario for one year，and the overall survival was a descriptive analysis，but the difference between the Nivolumab-treated arm and the control or the placebo-treated arm was very obvious，so the difference was increasing over time.And we had a 10-month improvement in overall survival，I think，was after three or four years in this trial which was presented.So，start treating early in the adjuvant setting，and I think we can select patients and prevent the development of metastatic disease.On the other hand，this question always relates to biomarkers.The field of biomarkers is very wide，but we had a very interesting presentation here from the IMvigor011 trial，which had a ctDNA approach.If they were positive，they were randomized to adjuvant treatment of Atezolizumab versus observation or placebo，and they had a ctDNA negative fraction which was not trial eligible.And here at the Congress，the ctDNA negative patients and their follow-up were presented，and it was very interesting that if a patient had a ctDNA negative status，the risk of developing a relapse of bladder carcinoma after cystectomy was very low.And the level of ctDNA was measured over time.If they turned positive from negative to positive ctDNA，then the risk of recurrence is there and increases.

 

Dr.Jens Bedke

Klinikum Stuttgart Katharinen Hospital