“We’re very， very excited about these results and certainly they need to be confirmed in a larger Phase II trial.”

 

enfortumab vedotin（ASG-22CE; ASG-22ME）是一种靶向结合素-4（Nectin-4）的抗体复合物。结合素-4广泛表达于不同的人类肿瘤细胞，特别是转移性尿路上皮癌（mUC）。Petrylak教授发现，97%的尿路上皮癌样本中均有结合素-4的表达，因此团队进一步开展抗-结合素抗体（连接到MMAE，一种微管蛋白抑制剂）的相关临床试验。

 

研究纳入既往接受化疗的mUC患者，给予不同剂量（0.5， 0.75， 1， 1.25 mg/kg）抗结合素-4治疗。结果取得了40%的总缓解率。其中，既往免疫检查抑制剂治疗失败患者中，缓解率为46%。伴肝转移患者中，缓解率为44%。“我们对这些结果异常惊喜，将继续进行更大临床样本的Ⅱ期试验来证实它的有效性。”

 

Prof. Petrylak: Enfortumab vedotin is an antibody drug complex， and what that recognizes is something called Nectin-4. Nectin-4 is expressed in a variety of different human cancers， particularly metastatic urothelial carcinoma. In fact， we found that 97 percent of the specimens that we examined for urothelial carcinoma expressed Nectin-4. So， we went forth with an escalating phase—one trial of the anti-Nectin antibody that was linked to MMAE， which is an antitubulin agent. 

 

We reached 1.25 mg per kilogram for three weeks out of four， and what we found was that these were patients who had previously been treated with platinum therapy for urothelial carcinoma. And we had about a 40 percent response rate. The responses were seen in about thirty percent of the patients who had prior check point exposure. Additionally， about the same percentage of patients had a response in liver. So， we’re very， very excited about these results and certainly they need to be confirmed in a larger Phase II trial.

 

 

“We are seeing a difference in PFS and that is significant and that， of course， met the primary endpoint.”

 

目前确有一些尚在临床试验阶段的药物，如一项针对ramucirumab的随机对照研究，比较抗-VEGFR-2药物联合多西他赛与多西他赛单药方案在既往治疗失败的mUC患者的疗效。Petrylak教授指出，这一研究结果即将问世，因为已经达到主要终点——无进展生存（PFS）。随着研究的不断进行，仍在等待其他研究终点的出现，期望明年能获得生存分析的相关数据。“但目前，我们已经看到了PFS的差异，这是相当可喜的。”

 

Prof. Petrylak: I can’t go into the details of this particular trial because of the fact that it’s only been released as part of a press release. But we did a randomized trial of ramucirumab， which is an anti-VEGFR-2 agent combined with docetaxel and compare that to docetaxel alone in patients who fail prior therapy with metastatic urothelial carcinoma. 

 

And I’m happy to report that as has come out in the press release， we’ve met our primary endpoint， which is progression-free survival. So， we hope to have survival data next year， but we’re still weighing that particular point as the trial is still maturing. But， we are seeing a difference in PFS and that is significant and that， of course， met the primary endpoint.

 

 

“ I think all of these need to be taken into consideration when you are considering your patient with bladder cancer.”

 

Petrylak教授认为，治疗方案的选择需要权衡药物的治疗作用与不良反应。铂类药物为基础的化疗是很有必要的，无论是否联合吉西他滨或者用MVAC方案，这是mUC患者的标准治疗。二线治疗方面，atezolizumab、pembrolizumab、nivolumab、divolumab等多个免疫检查点抑制剂可以考虑，它们已经被FDA批准纳入二线治疗。

 

对于不能耐受铂类药物化疗的患者，现在有两种FDA批准的新药，即pembrolizumab和atezolizumab，作为试验性治疗。能否使用铂类药物，取决于患者的肌酐清除率、有无合并神经系统疾病、心功能情况，当然还有体重下降情况等。“对于mUC患者，在选择治疗方案时，需要综合考虑以上所有因素。”

 

Prof. Petrylak: So， I think what you have to do is weigh the side effects versus what the drugs are. Still， at this point for patients， platinum eligible， platinum-based chemotherapy—whether it be in combination with gemcitabine or the MVAC regimen—is still standard of care. For second line treatment， atezolizumab， pembrolizumab， nivolumab，divolumab， all of the checkpoint inhibitors—five of them have been approved by the FDA for treatment as second line. 

 

In platinum-ineligible patients， there are two FDA approved drugs—pembrolizumab and atezolizumab—which are approved as frontline therapy. Then chemotherapy can fall on these patients. And， of course， platinum ineligibility is determined by the creatinine clearance， neuropathy， and cardiac function， as well has hearing loss. So， I think all of these