Alicia Morgans: Hi, I'm so excited to be here at SOGUG 2022, where I have the opportunity to speak with Professor Maria De Santis. Thank you so much for speaking with me.

Maria De Santis: Hello, Alicia. It's lovely to be here and meeting you in Madrid.

Alicia Morgans: It is wonderful to meet with you wherever we are around the world, and so nice to catch up. And I want to congratulate you on an excellent talk, and you really, I think, enlightened all of us, on the advances of the use of immunotherapy as a single agent, or in combination, in the perioperative space for urothelial carcinoma, thinking about neoadjuvant, adjuvant and all of the above. So can you tell us a little bit, let's start with neoadjuvant approaches. Can you tell us a little bit about, maybe just even define the need. I mean, which patients are already getting new adjuvant therapy, not necessarily immunotherapy, and is there a population maybe at high need that we could really do better?

Maria De Santis: Sure. So I think these questions are really important, because still, patients die of metastatic disease once they're diagnosed with muscle-invasive bladder cancer. So until now, new adjuvant chemotherapy, with a platinum combination, with cisplatin combination actually, has been a standard of care for many, many years. However, this is only a treatment for the cisplatin eligible population. But we know that 50, 40 to 50% of patients are not fit enough, and not eligible for that cisplatin combination. And for those patients, who actually do not have a perioperative systemic therapy in our recommendations, because there is no adequate data. So these patients would go immediately to definitive treatment of the bladder, which means surgery, or bladder preservation with chemo radiotherapy. So this patient population actually, is in need of a treatment that would prolong their survival, that would treat early micrometastatic disease, which is what we actually treat with the systemic therapy.

Alicia Morgans: So tell me, have there been investigations to look into immunotherapy in this setting, particularly for the cis ineligible population?

Maria De Santis: Yes, indeed. And the big advantage of immunotherapy of the checkpoint inhibitors is, that we don't need a very good, high GFR. The renal function is not so important. We can also give it with decreased renal function. And this is the issue in most of the patients with bladder cancer. So immunotherapy, either monotherapy or in combination, actually might have an important role for those patients.

And there have been trials with monotherapy, with checkpoint inhibitors, with pembrolizumab, or atezolizumab, or durvalumab, with the different kinds of products that actually showed activity. And in those Phase II trials, the activity was shown with pathological complete responses on the one hand, but also, with event-free survival. However, those trials were not randomized controlled trials, but they were single agent trials. Nonetheless, we have quite strong evidence, that in these patients, and mainly the cisplatin ineligible population was tested, that these agents are active. The pathological complete response rate is around 30, up to 40%, in those smaller scale Phase II trials.

Alicia Morgans: Well, that's actually much higher than we would expect from a TURBT alone. Right? So definitely, as you said, suggests some activity. There have been some studies looking at combinations with chemotherapy, immunotherapy and chemotherapy combinations, and trying to understand whether maybe even an adjuvant approach could be useful for patients. What else can you tell me about the perioperative treatment, and the use of immunotherapy with or without chemo?

Maria De Santis: Yeah, so there is a lot going on, actually. And there are combination trials in the muscle invasive bladder cancer setting, combining chemotherapy and immunotherapy, then followed by surgery and going on with immunotherapy. There are randomized controlled trials ongoing. We still do not have the read out. We are waiting for the results, actually quite eagerly. So these trials have two endpoints. The first endpoint is pathological complete remission rate, which is a very immediate, a very early endpoint of course, because it's only surgery after, let's say, three months.

But the second endpoint, event-free survival endpoint, is maybe even more important, because still, we are not sure if the pathological complete response rate really goes, also confers into a survival benefit, at the end of the day. So these trials, of course, are important.

But it is quite interesting. The rationale behind is not so clear, because in the metastatic setting, when combining chemotherapy and immunotherapy, we saw some negative trials. So until now, we don't think that these combinations are actually synergistic. So let's see how this works in the new adjuvant and adjuvants of the perioperative setting.

Alicia Morgans: I think there is definitely a lot to learn. I'm excited for the trials that are ongoing. And there certainly has been some information that's come out. CheckMate 274, really looking at an adjuvant approach using nivolumab. This is something that has, I wouldn't say controversy. The data is what the data is, and we still don't have survival endpoint data yet. We just have a disease-free survival endpoint. But this has led, I think, to different labels, approvals, and recommendations and guidelines, around the world. And so I'd love to hear your thoughts on that data, and maybe how it also compares to other agents, other than nivolumab.

Maria De Santis: Sure. And as you said, this area is kind of a dilemma, or we see conflicting results. So to begin with, the CheckMate 274 trial tested nivolumab in a placebo controlled randomized trial. The endpoint was disease-free survival, the first endpoint. And this was a positive trial, and high-risk patients were included. A good percentage of patients, like 40%, had neoadjuvant chemotherapy before. And high-risk disease, the population was actually mixed with disrespect, still in the ITT population, a positive trial. And it was even more positive with a hazard ratio of 0.52 in the PD-L1 positive population.

The other trial was IMvigor010. And IMvigor010, atezolizumab, the PD-L1 inhibitor, was tested in a similar fashion, only it was not placebo controlled, but it had an observational control arm. And this trial was completely negative. And even the PD-L1 positive population was completely negative, with respect to the first endpoint.

We also saw secondary endpoint, overall survival, with atezolizumab, which was completely negative. And we have not seen the overall survival data with nivolumab, on the other hand, the positive trial. So the data is a little bit conflicting here, one negative study, one positive study, and we would really love to see the OS data with nivolumab in that setting.

Then, there is the issue about the approval of the drug. There is FDA approval for nivolumab in the adjuvant space here. The EMA took a completely different decision. They picked out the PD-L1 positive population, a subgroup. This actually caused a little controversy, where worldwide, why pick out that subgroup? And I actually was more impressed about the data with the subgroup of neoadjuvant pretreated patients, then surgery, high risk, and then going to nivolumab, where the data was actually pretty convincing. So it is a little bit unclear to me why these decisions were taken by the authorities. Still, the data are as they are, as you said, and we have to live with it. Nonetheless, in the ESMO guidelines, we actually decided not to give a level 1A recommendation as of yet, because there is still that controversy around.

Alicia Morgans: So I guess we'll have to see. So it's just interesting the way that we see all of these, the same trial leading to different outcomes in different parts of the world. And hopefully, we'll have good, the best outcomes we can for survival to help patients, and then maybe more consistency across the guidance and the recommendations.

So what else are you thinking about? Anything else that you want to mention? When it comes to immunotherapy in this perioperative space for muscle invasive urothelial carcinoma, what should our take home messages be?

Maria De Santis: Well, I think first of all, the neoadjuvant setting is a great space for a window of opportunity trials. I think we should put our patients on trials to advance the field, because the immediate endpoint with pathological complete remissions, or translational research with the specimen after a certain treatment within two or three months before surgery, can lead us, and can help us to develop new treatments.

The second thing is that, the most exciting trials actually are combining new agents that are very active with immunotherapy. And here, I want to refer to the enfortumab vedotin with pembrolizumab, for example, which has the highest ever seen response rates in the metastatic setting. In cisplatin unfit patients, for example, 70, 80% response rates, which has never been seen with a platinum combinations. So this combination put into the neoadjuvant space is very exciting. And this is yeah, quite some trials are out there, actually testing this combination, and I'm very excited about that.

Alicia Morgans: Wonderful. Well, I'm excited too, and I so appreciate you sharing your time and your expertise to go through a bit of a convoluted topic, but one, of course, that's very important for our patients. Thank you so much.

Maria De Santis: You're welcome. Pleasure.