编者按：在刚刚落幕的2023欧洲肿瘤内科学会年会（ESMO 2023）上，来自意大利IRCCS圣拉斐尔医院的Andrea Nccchi教授在迷你口头报告现场，报告了一项2b期临床研究，使用一种全新的膀胱内局部化疗给药系统TAR200，有望成为高危非肌层浸润性膀胱（HR MIBC）患者降低疾病复发的治疗手段；除此以外，本次大会还报道了另一种类似的膀胱内局部靶向治疗给药系统TAR201，以及ADC联合免疫一线治疗晚期尿路上皮癌的EV-302等重磅研究。Andrea Nccchi教授在接受《肿瘤瞭望》的采访中分享了他对这些最新研究的看法。

Andrea Nccchi教授：TAR200是一种新的膀胱内递送系统，可以通过一根硅胶管稳定释放吉西他滨，也就是说，硅胶管渗透性地将吉西他滨烯释放到膀胱中。这是一根细小的硅管，可以通过膀胱镜将其置入膀胱，因此一种非常简单的内窥镜手术，每三周取出一次，重新充药，然后更换到膀胱中。因此，通过这种方式，我们可以让肿瘤持续暴露于药物中，这是成功的关键。因此，肿瘤暴露于药物的总时间似乎比其他化疗或其他药物的给药方式更长。

 

 

Oncology Frontier:Could you introduce what kind of new delivery system TAR-200 is?

 

Dr.Andrea Nccchi:TAR200 is a new intravestical delivery system that allows a stable release of gemcitabine through a silicon tube that is，that osmotically released the gemcitabine into the bladder.It’s a small silicon tube that is put into the bladder via a cystoscopy，so a very easy endoscopy procedure，and is removed every three weeks，recharged and then replaced into the bladder.So this way we can allow a continuous exposure of the tumor to the drug，and this is the key of success，so the total exposure time for the tumor to the drug seems to be，to make the key and the differences compared to other ways of installation of chemotherapy or other drugs in this disease.

Andrea Nccchi教授：SunRISe-1是一项平台研究，旨在评价TAR-200在不同疾病分期膀胱癌单药疗法或与免疫检查点抑制剂cetrelimab（抗PD-1药物）联合治疗。SunRISe-1是一项随机2b期开放标签研究，队列1患者接受TAR-200联合cetrelimab，队列2单独TAR-200，队列3接受单独cetrelimab治疗，还有一个额外的队列4正在招募患者。该研究入组患者为乳头状、高风险、非肌层浸润性疾病的患者。重要的是，队列1、2和3还纳入了原位癌（CIS）患者，这些患者都经历了卡介苗（BCG）灌注失败，可以定义为BCG无反应性疾病，且拒绝或不适合根治性膀胱切除术。此处报告队列2数据，入组患者前24周接受TAR200每三周一次，然后改为每12周一次直至第96周。主要终点是总体的完全缓解（CR）率，在第24周和48周通过尿液细胞学和活检进行评估。终点的定义是非常严格的。

 

△SunRISe-1研究设计及队列2主要终点（CR率）和安全性

 

Oncology Frontier:Could you please share the SunRISe-1 study you presnented at this congress?What is the clinical significance of this study?

 

Dr.Andrea Nccchi:Well，the SunRISe-1 is a part of a platform study testing TAR-200 as monotherapy or in combination with the immune checkpoint inhibitors or Cetrelimab(anti PD-1 agent）in various disease stages.The SunRISe-1 in particular is a randomized phase 2b open-label study in which patients are randomized to receive a TAR-200 in combination with the Cetrelimab in cohort-1，TAR-200 in monotherapy in cohort-2，or Cetrelimab in monotherapy in cohort-3.There is an additional cohort of patients that is included in this currently enrolling patients that is cohort-4.It is included in patients with the papillary，high-risk，non-muscle invasive disease.Importantly，cohort-1，2，and 3 are included in patients with the crinoma in situ disease，to component with or without a papillary disease who have already experienced a BCG failure and who has already received a sufficient number of BCG intravascular in order to define them as having a BCG unresponsive disease.The standard of care for experimental radical cystectomy and these patients are refusing or unfit for radical cystectomy.The reported data pertains to the monotherapy cohort，specifically Cohort 2，where TAR-200 is administered every three weeks for the initial 24 weeks and subsequently every 12 weeks until week 96.The primary endpoint is the complete response rate，rigorously assessed centrally through urine cytology and biopsies at weeks 24 and 48.It’s essential to note the stringent definition of this endpoint.

 

Andrea Nccchi教授：所以TAR210是一种类似的给药方式，我们局部输送的不是化疗，而是抗FGFR靶向治疗厄达替尼。这项研究是评价TAR210在中危非肌层浸润性膀胱癌患者治疗的研究。主要终点是无复发生存率，目前随访非常短，在该患者人群中的无复发生存率超过80%（82%），因此相当有希望。根据FGF受体（FGFR）分子改变筛选患者。目前我们的（SunRISe-1）研究还没有关于入组患者PD-L1表达的信息。当然，这是正在开展中的研究，从推测来看，PD-L1在这个患者群体中的表达率应该很低。

 

 

Oncology Frontier:For LBA 104 presented at the same session，TAR-210 was used for NMIBC with FGFR alteration.Does your research also include analysis of biomarkers such as PD-L1?

 

Dr.Andrea Nccchi:So the TAR210 is a similar way，pursues a similar way of delivery in therapy，and basically in this case，we don’t have chemotherapy，but we have a first targeted therapy that is delivered locally.TAR210 was a study which investigated the delivery of treatment in patients with intermediate risk，non-muscle invasive blood cancer.The primary point was their recurrence-free survival，and the initial data，but very short term，follow up quite promising，more than 80%relapse free survival in this patient population，so quite promising.These patients were selected according to FGF receptor molecular alteration.So basically，we don’t have at least at the moment information on the PDL1 expression of these patients.Of course，it’s something that is being，is it the pipeline of the analysis of the study，but we still do not have，and presumably，the PDL1 expression should be low in this patient population.

 

Andrea Nccchi教授：是的，这些疾病进展患者仍然是存活的，因此有大量的投资、大量的临床试验旨在开发新的全身治疗或膀胱给药的新型药物。此类患者涵盖了高危NMIBC和早期MIBC，是一种潜在的致命性疾病，有很多研究正在探索新的治疗组合，尤其是在一线治疗中提供新的标准治疗组合，如ADC联合免疫治疗，但也有像TAR200、TAR210这样的新型联合治疗，即膀胱内给药联合免疫治疗等全身治疗的组合。因此，我们的重点是治愈患者，避免疾病进展和进行根治性膀胱切除术，也就是在使患者得到膀胱保留的同时，达到治愈目标。

 

Oncology Frontier:At this congress，you also conducted the speech on the progression of NMIBC to MIBC.What implications does this progress have for our clinical treatment?

 

Dr.Andrea Nccchi:Yeah，the point of disease progression in this patient population is still alive，and this is the reason why there is a huge investment，and there is a large number of clinical trials that are investing in the searching for new drugs systemically or intravestically in this patient population，population across the border of high risk，non-muscle invasive disease，and early muscle invasive disease.So this is a potentially deadly disease，so there is a lot of research ongoing，testing newer combinations，in particular testing the combination that provided a new standard of care in front line metastatic setting like ADC and immunotherapy combination.But there are also combination of therapies like TAR200，so intravascular therapy and systemic therapy or combination of immunotherapies.So the point here is to try to cure the patients and to avoid the progression of the disease without going towards radical cystectomy.So sparing the bladder to these patients and achieving the goal of a cure.

 

Andrea Nccchi教授：作为肿瘤学家，我们都对EV-302研究的数据印象深刻。enfortumab vedotin联合Pembrolizumab（EV-Pembro）用于转移性膀胱癌患者一线治疗，将可能改变我们的治疗方式。免疫疗法阿维鲁单抗联合基于顺铂的一线化疗也很有趣，（JAVELIN Bladder 100研究）也达到了OS显著改善（23.8 vs.15.0个月，HR 0.76），但改善幅度低于EV-Pembro（31.5 vs.16.1个月，HR 0.47）。但我想，至少对选定患者来说，这种组合仍然有机会。下一次会议我们可能会关注于患者选择和生物标志物，这可能使我们能够确定最适合某些治疗策略的患者。因此，在不久的将来，患者的选择和治疗方法的选择是关键。非常感谢。

 

△EV-302研究设计及PFS和OS结果

 

Oncology Frontier:During the whole congress，there are many new researches and new discoveries on the urothelial cancer，which one impressed you the most?

 

Dr.Andrea Nccchi:Well，of course，as oncologists，we are all impressed by the data of EV-302 study.So，in enfortumab vedotin and Pembrolizumab，in front line，metastatic setting that changed the way and potentially will change the way we conceive the treatment of patients with a metastatic bladder cancer.There has been also that interesting with the combination of immune therapy avelumab and cisplatin based chemotherapy in front line.(JAVELIN Bladder 100)Also achieving the primary point with the magnitude of improvement in survival that was lower than that achieved with the EV-Pembro(EV-302).But there is still an opportunity I guess for this combination at least for selected patients.Mainly we will work for the next meeting on the patient selection and on biomarkers that may allow us to identify the patients who are best suited for certain therapeutic strategies.So patient selection and therapy selection is the key in the near future.Thank you.

 

Andrea Nccchi

意大利IRCCS圣拉斐尔医院

Andrea Necchi教授主要研究泌尿生殖系统恶性肿瘤的治疗。从2020年11月起，担任圣拉斐尔生命健康大学肿瘤学副教授，并兼任意大利IRCCS圣拉斐尔医院科学研究所泌尿生殖系统肿瘤学科负责人。

Andrea Necchi教授及其研究团队专注于整个泌尿系统恶性肿瘤领域，主要致力于开发新型实验疗法的全阶段临床试验。他是多项泌尿系统恶性肿瘤免疫联合疗法1-2期学术试验的主要研究者，也是首位“Gianni Bonadonna肿瘤新药开发奖”获得者，并曾四次获得ASCO攻克癌症基金会颁发的优秀奖。