Thomas Powles: Hey, how are you?
Patrizia Giannatempo: Hi. Hi, Ashish.
Ashish Kamat: So we had a really fabulous and timely debate between the two of you at EAU at our trademark debate session, Rapid-Fire. I think that was the topic that was probably most highly anticipated with all the data that's come out, the change in treatment paradigms, people going on either side of the treatment fence, and some people advocating for picking and choosing different parts of the whole equation. And I think both of you did such a phenomenal job that it's really great to have you here today. We'll start off with you going through your presentation, but I'm really looking forward to the discussion at the end of it. So, Tom, whenever you're ready.
Thomas Powles: Thank you. I'm going to talk very briefly about immune checkpoint inhibition for all in muscle-invasive bladder cancer. I think we have been pursuing a one-size-fits-all approach in the recent past. It's been really focused on cystectomy. We've described other treatments as icing on the cake, neoadjuvant chemotherapy associated with modest 5% survival advantages, not widely adopted from a global perspective, adjuvant trials never achieving overall survival, and chemoRAD being an alternative for cystectomy in most places as for those patients with poor performance status. I know that's not universally true, but that's probably the historical position that we are in. And here is one of the sobering neoadjuvant chemotherapy curves, which shows that, actually, 50% of patients or less than 50% of patients making it to five-year survival. And so this is a lethal disease and has been a really lethal disease, continues to be that. However, we have seen some neoadjuvant trials recently, or with immune therapy, which have transformed that landscape. But before we get there, we should really talk about what happened with adjuvant immune therapy. So there've been three adjuvant immune therapy trials with nivolumab, atezolizumab, and pembrolizumab. None of these trials have achieved overall survival that's statistically significant.
And that survival goal is really important for two reasons. Number one is, of course, we're over-treating. Probably half of the patients are getting therapy who don't need it. Those patients are not destined to relapse, but have a 15% chance of life-changing toxicity. And number two is in this setting, unlike in the metastatic setting, if we're not making patients live longer and we're exposing toxicity, is it easier just to give treatment in the metastatic setting? And so for that reason, a selected approach using ctDNA is attractive. This is the adjuvant setting for those patients that haven't prior had immune therapy. This is the first retrospective analysis from IMvigor 010. This showed us that the ctDNA-positive patients in dark blue and dark red, they have a very high chance of relapsing. That's about half of the patients. And atezolizumab reduces the risk of death. While those negative patients, they're at much lower risk. And of course, this turns a negative trial into a positive study by sparing those patients that don't need therapy, life-changing toxicity. It's also important to remember in this space that immunotherapy doesn't work in everyone. It's not like chemotherapy and testis cancer. So those patients at lower risk, those patients, the benefit of immune therapy is going to be relatively modest. Those patients at much higher risk, all of whom are destined to relapse, that's a population in which we can focus on.
However, that wasn't adequate. We had to do a prospective study to show that that was the case. And here we do the randomized IMvigor011 trial. Patients who are positive or who become positive post-surgery in a prospective manner are given atezolizumab or placebo. The negative patients are given no treatment. Patrizia's going to talk in more detail about this study, but as with the retrospective analysis, we did achieve a survival benefit for the first time by selecting patients. And of course, if you've got a survival benefit in one group of patients, inevitably the other group of patients are unlikely to have that benefit. And the reason why is so few of these patients end up dying of bladder cancer or indeed relapsing. As I said, Patrizia's going to talk about that in more detail. But what I wanted to talk about, really, was these three perioperative immune therapy trials. And actually, I'm going to start on the right-hand slide of this curve with the Niagara study. In this study, gem/cis chemotherapy was the control arm. Neoadjuvant chemotherapy, here, we added in durvalumab perioperatively, four cycles before, eight cycles afterwards. We showed a path CR rate increased by 10% compared to platinum chemotherapy.
We showed an OS hazard ratio of 0.75, a 25% reduction in risk of death. So here, unlike in the adjuvant setting, chemotherapy plus durvalumab is associated with a significant survival advantage for the first time. The first perioperative trial to achieve that goal, 88% of patients getting cystectomy, there were no increased toxicity signals that pre-made surgery more complicated. And you can see here 71% of patients starting the adjuvant period and 54% of those patients completing that adjuvant period. And by the way, that's become a global standard of care. It's NICE approved. We're even giving it in the UK. But with these two other trials that I wanted to talk about with perioperative enfortumab vedotin and pembrolizumab, essentially nine cycles of treatment with surgery somewhere in the middle, one of the trials compared to cystectomy alone, and the other trial compared to gem/cis. Both of these trials also achieved that goal, that big goal of overall survival with hazard ratios of 0.5 and 0.65. So they're both statistically significant. Importantly, you've got path CR rates of 56 and 57%. So these path CR rates are above what we would see historically, above the 37% we saw with platinum chemotherapy. It's a very impressive result. I think that probably makes EV-pembro, with surgery somewhere in the middle, the standard of care. I think the Niagara approach with durvalumab is a second best behind that and far superior to the other approaches. But nevertheless, those path CR rates above 50%, really impressive.
And then that two-year OS landmark, 80%, 87%, 82, cross-trial comparison is not particularly helpful. But when you look at that two-year OS and you compare that to what I showed you before with neoadjuvant chemotherapy, where actually only 50% of patients making it through to five years, only 60% at two years. This really shows this massive advance we've made in muscle-invasive bladder cancer. And thank you, very much. Over to you, Ashish.
Ashish Kamat: Thanks, Tom, for, as always, tacking a very complex question and distilling it down in a way that folks can really understand. We're going to give Patrizia the opportunity to respond with her counter argument, which I don't think really was a counter agreement, right, Patrizia? It was more a supplementary, "This is my viewpoint." I really enjoyed that, too. So looking forward to hearing what you had to say.
Patrizia Giannatempo: So thank you for this kind of invitation. And once again, I will stress again what Tom said before. So I think we now discuss after very effective neoadjuvant chemotherapy, chemo plus immunotherapy, and we discuss much more in detail about adjuvant part. So we want to focus the next three minutes on the yellow diamond. That are the number of patients that can benefit from the use of immunotherapy in this case, nivolumab in CheckMate 274, when we use an adjuvant part. So we want to really don't overtreat a good number of patients. So back again, this is NIAGARA study. I think one of the hugest trials that we perform in perioperative setting. And just focusing on adjuvant part, we know that pCR historically is our dream, what we want to find after neoadjuvant treatment. But what we can discuss about patients that reached pathological complete response and the role of identification of high-risk patient for adjuvant part. NIAGARA present placebo group analysis from time of radical cystectomy. So afterwards, that means exactly the adjuvant space for our patient. As you can see here, of course, patient with pathological complete response, they have very good disease-free survival compared to the other patient. But even in pathological complete response patient, we still have patient that benefit from the use of immunotherapy.
And we need to identify who are these specific patients to candidates to adjuvant immunotherapy or just follow up. I think again, what Tom said before, look at ctDNA could help us to identify high-risk patient in adjuvant setting. I really like the RETAIN-1 and RETAIN-2 trial. They presented the result at ASCO GU this year, San Francisco. The RETAIN-2 is a sort of bladder-sparing strategy where they give neoadjuvant chemotherapy in RETAIN-1 and chemo plus immuno in RETAIN-2 trials. But here we will discuss in particular the results of ctDNA. They collect ctDNA in baseline after neoadjuvant treatment and in the RETAIN-2 three and six months. And what they present at ASCO GU are these results. I find it's very interesting because they identify, put together these two trials, all these patients. They identify three different categories of patient. First of all is the pink one, the patient with persistent ctDNA positivity during all this strategy. As you can see here, they have very bad metastasis-free survival. And then we have an intermediate risk category of patient that are patient with ctDNA clearance. That means were negative and then become positive or vice versa. And then we have ctDNA-negative patients, so patient that from baseline and post neoadjuvant treatment, they are ctDNA negative. That means they are completely different outcome, completely different patients. So in my mind, in our mind, start to think about maybe we don't need adjuvant immunotherapy for ctDNA-negative. We already see that ctDNA persistent negative patient are patient that in any way have good outcome. And then once again, Tom present this trial and already mentioned before.
This is amazing trial, phase three trial where they decide to treat with immunotherapy only when the patient becomes ctDNA-positive in one year time. So again, ctDNA-negative patient, they have very good outcome in disease-free survival and overall survival. But when we look at the clearance, we can see that, again, we have two different type of patients. Patient with present a ctDNA-negative, they have very bad outcome in terms of disease-free survival. And when we have a patient that where ctDNA negative when they enter in the study, and then during the follow-up, during this one year, they become ctDNA positive, again, the disease-free survival and overall survival is still not good as persistent ctDNA-negative patient. So early ctDNA positivity is associated with inferior clinical outcomes. So put together this data. What happened when we use immunotherapy? When we use atezolizumab in this trial, and we have a patient with ctDNA-positive initial tests, so the first test, even this case when we use immunotherapy atezolizumab, we still give to this patient advantage in terms of disease-free survival, maybe over survival as well. And when we look at ctDNA-positive in subsequent tests, so negative at the beginning, then positive one year time, again, immunotherapy, in this case atezolizumab, have some role to improve disease-free survival and overall survival. And then just to mention about this trial, the modern trial, is USA trials where they try to answer different question. For ctDNA-positive, they try to answer the question, do we need just immunotherapy or we need to give more treatment? Do we need to intensify the treatment for ctDNA-positive?
Because maybe we can give better outcome when we use more than one drug. And when we look at ctDNA-negative patient, they are the code B, again, they try to answer the question, we can try to use a risk-adaptive strategy only in case we have ctDNA-positive. In this case, they test nivolumab instead of atezolizumab. So just a conclusion, I think risk-adaptive strategy is the way to reduce overtreatment, as even Tom said before. And we start to think even in [inaudible 00:14:57] carcinoma, we start to think about minimal residual disease detected by ctDNA. That could be the way to give more information behind the pathological complete response. The ctDNA assessment is fundamental, I think even particularly the dynamic monitoring. We have seen how to check for one year ctDNA in our patient can detect a very different type of patient with different outcome. So I thank you for this invitation, and I think it's the time to start the discussion.
Ashish Kamat: So, Patrizia, wonderful as always. And thank you for taking the time. I think the two of you have really distilled the data down in such a clear-cut manner that I'm going to put you both on the spot a little bit just to bring out certain salient points. So, Tom, let me start with you. I mean, you've been a champion of looking at prognostic predictive markers and personalizing therapy. And with all the data that you have in front of you, if you have a patient tomorrow, young, healthy, muscle-invasive disease sitting in front of you and says, "Dr. Powles, I want the best chance of long-term cure," What are you telling that patient?
Thomas Powles: The question is very easy. I would say, "10 years ago, half the patients were dying of this disease within five years. We now, with EV-pembro, with surgery in the middle, that has reduced to about 20% rather than 50% of patients dying. You should have EV-pembro nine cycles, surgery somewhere in the middle, and I wouldn't focus too much on the details of the other potential approaches right now. If someone tells you to do it differently, they haven't got evidence to support that being the same. Now, of course, there'll be lots of people with different ideas, but at the moment, that is the best way of you being alive in five years' time."
Ashish Kamat: I'm so glad you said that because as... I mean, again, you and I have talked about this, and you've been very vocal about this on many, many platforms. We need to study this, but we're not there yet. And if you jump into this with unbridled enthusiasm, without evidence, our patients are going to suffer. So I'm glad you said what you just said. Recognizing that, Patrizia, what do you tell a patient? Are you in clinic now doing risk-adaptive therapy or are you saying, "This is our evidence. Let's follow it"?
Patrizia Giannatempo: Yeah. I mean, I still use to speak with the patient and say, "Okay, we should base our practice on evidence." Of course, I will press the patient to go through enfortumab, pembrolizumab plus radical cystectomy. But to be honest, the number of patient that ask you about bladder preservation is increased nowadays. I think even there is a lot of news, a lot of discussion even between patient, between a cessation. So first of all, I try to convince my patient as much as possible that I want he stay alive for a long time and the signs, the medicines based on level of evidence. So perioperative treatment, systemic treatment with EV-pembro and cystectomy. If the patient asks me, and he complete aware about the risk of make a personalized strategy, we can use ctDNA, all these stuff. But first of all, radical cystectomy plus perioperative systemic therapy is the level one of evidence for this young patient.
Ashish Kamat: Great. So now we got that out of the way. Let me pick your brains a little bit. So, Tom, you have the same patient sitting in front of you and saying, "You know, Dr. Powles, I have the small tumor in my bladder. Yes, it's muscle-invasive. I really don't want the toxicity of any systemic therapy. Can you guide me if I could avoid neoadjuvant therapy?" What is your response there?
Thomas Powles: I mean, I would ask them to speak to the surgeons and ask them to have a long discussion about the ins and outs of cystectomy. That's not without significant adverse events. I think patient information's important. I'm not necessarily a great fan of complicated issues around patients driving their decision-making unless they really are really well-informed. And if you come to me and said, "Look, I like this part of the treatment, but not that part of the treatment," I'm going to say, "Well, you're probably going to get an inferior outcome, number one. And number two, it's not like nephrectomy where you're in and out and you're walking around a couple of weeks later and six weeks you're back to normal. After a cystectomy, you may not get back to that normal state that you think you will." And of course, all of these big operations have got their own problems. Don't get me wrong, systemic therapy is associated with life-changing toxicity, but so is big surgery, including cystectomy. So I'd put it back to you and said, "Why do you only want part of this treatment that seems to work very well?"
I would say that's risky. And of course, in the past, when we were less sure about the effect of life-saving toxic treatment, early immune therapy, clearly in three randomized trials, all got over survival, one of them has a hazard ratio of 0.5 compared to surgery alone, I would say you're going to double your outcome. You go down that 905 route, the cystectomy alone, you compare that to the EV-pembro arm, that OS has a ratio of 0.5. You're doubling your risk of death associated with doing it your own way.
Ashish Kamat: And, Patrizia, the same patient comes to you after undergoing the neoadjuvant part. Let's say they got three cycles, had surgery. They're doing great. They have no toxicity, no side effects, path CR, like you said. ctDNA is completely negative. And they're saying, "Why do I need to continue on toxic therapy?" How do you convince them to stay on it?
Patrizia Giannatempo: I will convince to say, "Okay, we can manage all the type of toxicity. We want to give your lifelong. I want to see you old," because we are talking about young patient, not 85-years-old patient. So I will convince the patient that even the adjuvant part we can manage together in case it can happen some toxicity. We can manage. And normally, I use patient a lot to speak each other to see what's happened because sometime the patient take decision based on the fear of toxicity, not really based on real experience or what they really knows. So I really push go ahead with adjuvant part because he's young, he has a very long life in front of him. So is could be different in case I have, again, 80-, 75-years-old man and could be different in this case.
Ashish Kamat: So let me give you both a question, and answer that, please. And then just give us your closing thoughts, your words of wisdom to the audience. The question I'm going to ask you is something that we hear all the time from our folks on the radiation oncology side. I love them. I have great relationships with them. But when they come and tell me, "Okay, we're going to give the neoadjuvant therapy. Dr. Powles is going to give that. Then let's radiate the patient and then send them back for the adjuvant part. Like, replace cystectomy with radiation without having done the trial because it should be the same," what's your response, Tom? And how do you address that?
Thomas Powles: I'd like to see trials with this that are going to happen. We're going to see those studies. We are going to move to an environment where we're going to be asking questions, strong questions, robust questions, big trials, bladder-sparing approaches, radiation rather than surgery approaches. Let's do those studies together. Let's get the robust data. And when we know what we're doing, we can then give patients an informed decision. At the moment, moving from this huge progress that we've made, and then adapting that to say, "Well, if we do it in a whole string of different ways, we'll get the same results," we're not there yet. So a series of one at a time robust questions, we're going to do some bladder-sparing trials. We're going to do some radiation trials. We're going to do lots of different studies. At the moment, we've made a huge step. Let's maintain that progress.
Ashish Kamat: Great. Well said. And, Patrizia, final words from you?
Patrizia Giannatempo: Yeah. Again, totally agree with Tom. I mean, we don't have data about that. I mean, in Europe, it's not possible because it's not allowed. So even if I could prescribe, there is no evidence. So I will stress to give... If we start with trimodality therapy, we should stay on level of evidence that we have, no more, because we don't know if we give more toxicity with any advantage. So again, no adjuvant immunotherapy after radiotherapy instead of cystectomy.
Ashish Kamat: Yeah. This is such an important topic. I really wish I had another 30 minutes, but I don't. So I just want to take a few seconds. Thank you both for joining us. Always a pleasure.
Patrizia Giannatempo: Thank you. You too.
Thomas Powles: Thank you, Patrizia.
Patrizia Giannatempo: Thank you, Tom.