作者：Tom Powles教授

 NO.3

"This is an area of controversy, level 1a evidence in the standard of care, the caveat that there is a significant chance of life-changing toxicity and other negative trials with similar drugs in a similar space."

肾透明细胞癌的围手术期治疗，尤其是辅助治疗，是有争议的。我们有一些新辅助治疗研究，但并不成功。我们不对肾透明细胞癌或任何肾癌进行新辅助治疗。不过，有一个问题是围绕着帕博利珠单抗辅助治疗的。帕博利珠单抗在肾癌中的辅助治疗已获得EMA和FDA批准。基于一项非常积极的随机三期研究，它被临床广泛使用。

KN-564研究入组了一千名患者，在中危和高危透明细胞肾癌中。五年OS点的无病生存DFS风险比为0.71，总生存风险比为0.66。在不同的数据截止时间上，OS的Δ值约为6%或7%。可以说是绝对获益。虽然这与10%到15%的重大毒性概率有关。但也可以说，复发风险明显降低，总生存期明显获益，这对患者来说很有吸引力。

Perioperative therapy in clear cell kidney cancer, particularly adjuvant therapy, is controversial. There have been some neoadjuvant trials but they've not been successful. We don't give neoadjuvant therapy in clear cell kidney cancer or indeed any kidney cancer. However, there is an issue around adjuvant pembrolizumab. Adjuvant pembrolizumab in kidney ancer is EMA and FDA approved. It's widely given and widely used based off a very positive randomized phase 3 study. 

KN-564 has a thousand patients included. It's intermediate and high-risk clear cell disease. The hazard ratios for disease-free survival at the five-year OS point is 0.71 and the hazard ratio for overall survival is 0.66. There's about a 6 or 7% delta in OS depending on the data cut that you look at. Absolute benefit. And although that's associated with a 10 to 15% chance of life-changing toxicity, it's also fair to say that with a clear reduction in the risk of relapse and a clear overall survival benefit, this is attractive for patients.

关于后续疗法还存在一些争议。在我看来，我们并不擅长收集后续疗法的数据。事实上，对于那些复发的患者，并非所有患者都会立即接受免疫治疗。对于复发风险较高的患者，我认为会有很多患者接受手术、放疗或舒尼替尼，这是完全合理的。

因此，我反对那些说所有患者都应该在复发时接受免疫治疗的人。我认为事实并非如此。我将这组数据中的后续治疗视为一个不断发展的问题。那么，如果帕博利珠单抗辅助研究是阳性的，为什么阿替利珠单抗辅助研究、纳武利尤单抗辅助研究以及，纳武利尤单联合和伊匹木单抗辅助研究都是阴性的呢？

There is a small amount of controversy around subsequent therapies. It's my opinion, for what it is worth, that we're not great at collecting data for subsequent therapies and indeed in those patients who relapse not all patients will immediately get immune therapy. In good-risk relapse, and I think there'll be many patients, perhaps surgery, radiotherapy or sunitinib are entirely reasonable.

So I push back on those patients or on those individuals who say all patients should have immune therapy at relapse. I don't believe that to be the case. And I look at subsequent therapy in this data set as an evolving field. So if adjuvant pembrolizumab trial is positive, how come the adjuvant atezolizumab study and the adjuvant nivolumab study and the adjuvant nivolumab and ipilimumab trials were negative?

老实说，在研究设计上，这些研究的相似之处多于不同之处。虽然纳武利尤单抗的疗程只有一年，而阿替利珠单抗是一种PD-L1抑制剂，不是PD-1抑制剂，而且我们知道它们在肾癌中的疗效不如PD-1抑制剂。顺便说一句，尿路上皮癌的情况并非如此。不过你也可以说，这些研究中还是有一些值得特别思考的地方的，尤其是伊匹木单抗联合纳武利尤单抗。

为什么伊匹木单抗联合纳武利尤单抗是阴性而帕博利珠单抗是阳性？当然，研究是不同的。它们的实施方式略有不同。它们也是不同的药物，这一点很重要，我完全不是在说帕博利珠单抗明显优于纳武利尤单抗——我们没有数据能证明这一点。如果你看一下亚组分析，就会发现在肉瘤亚组和PD-L1亚组中，伊匹木单抗联合纳武利尤单抗的疗效优于对照组，这表明该药物确实在发挥作用。那么阿替利珠单抗的研究呢？PD-L1阴性的部分让情况变得更加复杂了。

Well, there are more similarities than differences in the trial design to be honest with you. Although nivolumab was only given for one year, and atezolizumab is a PD-L1 inhibitor, not a PD-1 inhibitor, and we know they've performed less well than the PD-1 inhibitors in kidney cancer. That's not the case in urothelial cancer, by the way. However you could say we should have seen something within those trials, particularly Ipi/Nivo. 

How can Ipi/Nivo be negative and pembrolizumab be positive? Well of course there are different trials. They were performed in slightly different ways. They're also different drugs and that's important to remember, although I'm not suggesting, for a second, that pembrolizumab is clearly better than nivolumab. We have no data to say that's the case. If you look at the subset analysis you can show in the sarcomatoid subgroup and the PD-L1 subgroup Ipi/Nivo performing better the control arm, suggesting the drug is actually doing something. What about the atezolizumab study? Well the PD-L1 negative component makes it complicated.

我认为目前可以讲的是，我们以前从未在转移性疾病中见到PD-L1药的研究在OS获得了阳性结果。因此，当我与患者交流时，我会说我们有一项阳性的研究，它具有显著的总生存期优势，绝对获益约为5%至7%，癌症复发的风险降低了30%。如果癌症复发，你将在免疫治疗或肾癌的其他治疗中度过余生，因此避免复发是件好事。虽然有百分之十到十五的概率会出现重大的毒性，但大多数人都能充分耐受这种药物。但我也会对他们说，我们也做过其他研究，但效果都不如这个好，很难解释为什么会这样。

I think it's fair to park that and say we've never had a positive PD-L1 study for OS previously in metastatic disease. However it's hard to get away from the positive nature of the pembrolizumab trial and therefore when I speak to patients I say we have a positive study, it has a significant overall survival advantage, it is about a five to seven percent absolute benefit with a 30% reduction the risk of the cancer coming back. If the cancer is to come back you'll spend the rest of your life on immune therapy or on treatment for kidney cancer so it's good to avoid that. And although there is a ten to fifteen percent chance of life-changing toxicity most people are able to tolerate the drug adequately. But I do also say to them we've done other studies which haven't been as positive as this and it's hard to explain why that's the case.

还有一项名为 "RAMPART "的研究，比较了观察组和度伐利尤单抗组，以及度伐利尤单抗联合tremelimumab组的治疗效果。我认为这是一项有趣的研究，我认为该研究可能会给我们带来一些帮助。但从根本上说，作为一种PD-L1抑制剂，我们认为它跟阿替利珠单抗研究是一个派系的。还有其他使用VEGF/TKI疗法的方法，如舒尼替尼、帕唑帕尼和阿西替尼。基本上，我们不会在这种疾病阶段使用VEGF/TKI辅助疗法或新辅助疗法，IL-2和细胞因子是过去一代的药物了，它们在这种情况下没有任何作用。因此，总而言之，这是一个存在争议的领域：辅助治疗帕博利珠单抗在标准治疗中拥有 1a 级证据。我向我的病人推荐这种药物，但也会警示他们，这种药物有相当的可能会导致重大的毒性，而且在类似的场景下也有其他类似药物的研究得到了阴性的结论。

There is a further study called RAMPART which compares observation with durvalumab, and durvalumab and tremelimumab in combination. I think that trial is an interesting study, I think that trial may help us a little bit but deep down being a PD-L1 inhibitor you would imagine it would fall into the atezolizumab group. There have been other approaches with VEGF/TKI therapy like sunitinib, pazopanib and axitinib. Essentially we don't use adjuvant VEGF/TKI therapy in this disease or indeed neoadjuvant and the IL-2s and cytokines an era from the past they have no role to play in this setting. So in summary this is an area of controversy—adjuvant pembrolizumab has level 1a evidence in the standard of care. I recommend it to my patients with the caveat that there is a significant chance of life-changing toxicity and there have been other negative trials with similar drugs in a similar space.

Many thanks.

非常感谢。

——Tom Powles

来源：Tom Powles微信公众号