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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center in Houston, Texas. We're welcoming today, from Milan, Italy, Professor Andrea Necchi, who is Chief of the Genitourinary Medical Oncology department at San Raffaele Hospital and Scientific Institute. Dr. Necchi really needs no introduction, he's done a lot of thoughtful work in various fields of urologic oncology, and today he's going to talk to us about some summary data that was presented recently, but also his thoughts on where are we and what are some of the new roads towards bladder-sparing strategies for muscle-invasive bladder cancer. So with that, Andrea, the stage is yours.

Andrea Necchi: Thank you, Ashish, and [inaudible 00:00:50] thank again, UroToday people for allowing me to be here today to discuss with you the next developments in the field of bladder-sparing approaches in muscle-invasive bladder cancer.

These are my disclosures.

So we will move through the most recent data that'd been presented and discussed during the last ASCO Annual Meeting. The data from trials combining immunotherapy with chemoradiation or immunotherapy combination with radiotherapy. The further approach, which is a study behind the need for using radiotherapy on bladder cancer and employing the strategy which may preserve the bladder with any additional radical local therapy, including radiotherapy, in selected patients. We will see the data and we will discuss, again, the data.

So let's start from the immunotherapy, immunoradiation studies. The two most recent studies that'd been presented are the Balar study and the IMMUNOPRESERVE Spanish trial. Combining, the first one, pembro and chemoradiation, gemcitabine and hypofractionated radiotherapy, and the second one, durva and treme with radiotherapy. The results are shown here. A small sample size, but very promising rate of complete responses in both trials and a promising rate of bladder-intact disease-free survival in both the studies. So initial data, also coupled with the good tolerability of the combination, that are in a good shape towards the developments of further trials for the larger efforts in the field.

In fact, there should be a lot of concerns, potentially, regarding the use of such strategies, the use of the sequence, the correct sequence that should be used when administering pembrolizumab or immunotherapy together with the radiation, the schedule of radiotherapy. The endpoint to use in such trials, and we'll discuss later in the next few slides, the issue related with the use and definition of the primary endpoint, and additional concerns that may be relative to the adjuvant use of any therapy combined to radiotherapy and the use of biomarker to select patients who are more likely to respond and to get benefit from the combined approach, which is still at the beginning of the journey and we don't have robust data in this regard.

There are, of course, key studies in this field that are running very well and are accruing well worldwide. The SWOG study with atezolizumab and chemoradiation compared to chemoradiation alone in T2-T4 N0 M0 urothelial bladder cancer patients. The study is running in the United States. The KEYNOTE-992, which is an international study led by [Merck 00:04:20], which is combining pembrolizumab and chemoradiation, comparing this combination with the placebo and chemoradiation and we'll see the data. If they may change, they will change [inaudible 00:04:35] the clinical practice of these patients. For sure, the data from phase II studies, as well as the data, and as well as the possibility to include patients in such trials is reinvigorating the interest, mainly by the oncologists and by urologists, towards the potential use of different strategies compared to the use of a neoadjuvant chemotherapy radical cystectomy, which is the most widely used standard in this field.

As I mentioned, there should be different ways of conceiving the consolidation therapy in the bladder after an induction period, or in any case, consolidation therapy on the bladder in these patients, the use of surgery, which kind of surgery, radiotherapy, and now immunotherapy, or observation in selected patients after an induction therapy.
The most intriguing data came from the neoadjuvant immunotherapy studies because from the phase II studies that have been conducted in the field of perioperative immunotherapy, is in particular in selected patients, like patients with the ctDNA-negative situation, or clearance of tumor DNA after a neoadjuvant period, or patients with claudin-low subtype in the PURE-01 study. There may be patients that could benefit long-term even from the short course, two or three courses on neoadjuvant immunotherapy followed by radical surgery. So the issue of biomarkers is still in place, and is still a matter of clinical research, mainly when applied to bladder-sparing approaches.

In the Galsky study, presented at this year's ASCO meeting, we had the proof of principle of the suitability of a strategy that imply the use of gemcitabine and cisplatin with nivolumab as induction period. In patients achieving a clinical CR assessed that by cystoscopy and biopsy and by clinical imaging, patients had to decide between moving towards an adjuvant immunotherapy phase or the radical cystectomy as a more standard of care. It's intriguing to know that the vast majority of patients who achieved clinical CR in the study decided towards the experimental arm. So this means that patients that are motivated to be included in clinical trials, promising studies, intelligently conducted, may be on our side in order to try to improve the field and to move the field forward.

Of course, there may be uncertainties in the fact that in these kinds of studies, the rate of complete response is lower, in this case 48%, compared to the use of a radical approach on the bladder cancer. If we remember the rate of CR with the immune-chemoradiation or chemoradiation alone is around 80%. but there may be some important consideration to make when looking at the long-term outcome of these patients because, in fact, if we look at the endpoint of bladder-intact disease-free survival, the very early data, that are still unstable because of the short follow-up period, are very promising, and are more or less in line with the literature of the benchmark of chemoradiotherapy data.

So this means, as is evident in this slide, we need to look at randomized studies. Here, we made a digitalized comparison of published [inaudible 00:08:49] curves from the Nick James study, for example, BC2001, comparing this benchmark study with the early data presented with the two immune-radiation studies. In particular, with the Balar study, which is the orange curve here, the data seem to be very promising and are, in fact, very promising. But if you look at the benchmark chemoradiation alone, there doesn't seem to be any huge difference in between chemoradiation and the immune-chemoradiation to justify the use of immunotherapy. So we to have a randomization, we need a randomized study, so we definitely need the data from the two randomized study that I've shown before. But the contribution of immunotherapy is still a matter of debate, of clinical research, and we need longer follow-up time.

It's interesting also to note that in the PURE-01 study, patients who achieve a clinical CR and were operated, benefited with a one year relapse-free survival on 98% compared to 78% of the Galsky study. So it seems that by avoiding radical therapy of the primary tumor, in this case, a radical cystectomy, we are achieving, at the same time, promising data, but it doesn't seem to be so promising, or so good, compared to the data from the benchmark literature. So the benchmark of cystectomy and the neoadjuvant therapy or chemoradiotherapy is still hard to beat, and we need the randomized studies.

One of the final point that I would like to make in my considerations and in discussing such studies, is related to the use of the clinical endpoint. It's interesting that we are struggling against the need for tumor biomarkers, of circulating tumor biomarkers, like ctDNA. But as a matter of fact, we lack a robust clinical endpoint towards which we can test any biomarker. If you look at the complete response definition across studies, it's not homogeneous. Most of the studies look at the complete response meaning a complete absence of any viable residual disease, but there are studies that include in the definition, like in the SOGUG study, the definition of complete response included the presence of residual non-muscle-invasive disease, or in the Galsky study, the residual low-grade and non-muscle-invasive disease was included in the definition of complete response.

So we need harmonization of the endpoint, and also the long-term endpoint of survival needs, equally, homogenization and we need to be consistent in terminology across studies, because if we look at the literature also, we have different definition using different pivotal studies, key studies, like the UK studies using locoregional disease-free survival definition or invasive locoregional disease-free survival definition, which is not completely overlapping with the definition of bladder intact disease-free survival that has been used in the Balar study, for example, or in other US studies. For example, the inclusion or not of the distant metastasis as an event, or the need for cystectomy as an event, or the non-muscle-invasive relapse in the bladder as an event. All these issues should be harmonized and we should be consistent in the terminology, first of all, and in the practical definition of the use of the endpoint in clinical trials.

The data of [inaudible 00:12:49] ctDNA have been already mentioned, and of course, this data from the IMvigor010 studies that are likely to change the way we approach the peri-operative therapy in the muscle-invasive disease may be also applied to radiotherapy studies in immunoradiotherapy or chemoradiotherapy studies in order to decide the [inaudible 00:13:14], for example, the use of an adjuvant tail of treatment.
So in conclusion, the [inaudible 00:13:22] that we could make from the data, the [inaudible 00:13:27] that have been presented recently, are mainly related to the endpoints, as I mentioned in the last few slides. Lastly, if our aim is to raise the bar towards the possibility of avoiding any radical local therapy on the bladder tumor, so the true definition of bladder-intact disease-free survival that, to me, means a survival without any therapy needed on the bladder, including radiotherapy, we probably need to raise the bar of the therapeutic efficacy. So we need longer follow-up, first of all, and probably higher rate of CR and higher rate of bladder-intact disease-free survival long-term, so we should invest on patient selection finally, and likely, on the combination of neoadjuvant to combine with immunotherapy and to combine possibly with the standard of care.
That said, I would like to thank you, again, Ashish and UroToday, and then open to discuss further with you on this data. Thank you.

Ashish Kamat: Excellent. Excellent talk, Andrea, as usual. We've had you on the UroToday platform talking about this with Alicia, and you've spoken about this before, so let me focus our time that we have on discussions that maybe you haven't had before. So first, I completely agree with you. The endpoints, the trial designs, all of these need to be harmonized, so we can actually make sense of it. I'm sure you're aware that SITC, the Society of Immunotherapy for Cancer, and the IBCG, International Bladder Cancer Group, we have an ongoing effort where we are actually in the process of coming up with unified endpoints, trial designs, et cetera, et cetera, with input from multiple stakeholders in North America and Europe. So it's a very, very important point that you bring.

The other point that you raised and you alluded to that a little bit, is patient perspective, right? Because ultimately we, as clinicians and scientists, design studies and trials based on what we think is best for our patient, but it's very, very important to get the patient's input and find out from patient groups, what would he or she want from their bladder. Because, like you said, if you have a therapy that allows you to keep the bladder intact, but then the patient has to have multiple procedures every three or six months with tumors that recur and repeated anesthesia, that's not a win necessarily. So with all that in mind, let me ask you, if you were to hypothetically say that a trial X that looks at bladder preservation is a win for you and the patient, what would that trial look like and what would the result or endpoint look like?

Andrea Necchi: It's a $1 million question and a very important question. I would say probably the most reliable opinion on this matter will come from a combined answer from clinicians, from myself, from you, and from all the people involved in the treatment of bladder cancer, and the patient advocates, as you mentioned. Probably the most reliable answer that [inaudible 00:17:08] is I don't know, because it's not necessarily true that we should know which would be the right trial design, because actually the clinical endpoints and the different clinical endpoints that I have shown you, may not be fully overlapping with the needs of the patients. And this is the reason why we usually struggle against the issues related to the superiority or inferiority of surgery versus radiotherapy, and in these discussions, endless discussion, we missed, for years, the involvement of the patients.

The Galsky study, actually, provide us the proof of concept, which is very important, related to the fact that the patients that may be on our side also when moving to a path which is full experimental, but which may completely change the way we conceive the treatment of this disease by overcoming any needs of radiotherapy or surgery or conventional therapy that is usually employed in this situation.
So I think that the ideal study doesn't exist today and should be defined at the table together with the patient, patient advocates, biologists, statisticians, and probably the best of the success is achieved when we are at the end of the patient journey and the patient is satisfied at the end, of the results that we have achieved, regardless of the final survival [inaudible 00:18:59]. But the patients come to an end with a high satisfaction and is together with us from the beginning to the end in the journey, and I think that using immunotherapy revitalized also this way of conceiving the way of treating patients also in the bladder-sparing approaches, and [inaudible 00:19:25] revitalized as discussed in the ASCO meeting with Balar, the way we conceive the use of alternative therapy or standard therapy, like radiotherapy.

So it's a completely different way of looking at our routine work outside of what we can do in a clinical trial. So a totally different way of conceiving our way of thinking, I would say.

Ashish Kamat: Great points, Andrea. Again, I want to thank you for being such a thought leader and having such an insightful discussion. This was great. Once again, thank you for taking the time and I know our audience will really enjoy watching your presentation and listening to your discussion. Thank you.

Andrea Necchi: Thank you for the invitation, again. Thank you.