Ashish Kamat: Welcome to UroToday's Bladder Cancer Center for Excellence. I'm Ashish Kamat, I'm a Professor of Urology at MD Anderson Cancer Center in Houston, and it's my distinct pleasure to be joined by two friends, colleagues, and experts in the field, Dr. Necchi from Milan, Italy, and Dr. Grivas from Washington, Seattle, here in the US. Welcome, gentlemen, and thank you so much for taking the time to join us today.

Petros Grivas: Thank you, Ashish.

Andrea Necchi: Thank you, Ashish. Welcome, everyone.

Ashish Kamat: So for today's purpose, each one has been given a side. It's a side that they actually believe in. But, for the purpose of this debate, they're going to believe in at the expense of the other. Essentially, Dr. Necchi is going to talk about how the evidence, even today in May 2020, favors checkpoint inhibition as neoadjuvant therapy. Then Dr. Grivas will give us his viewpoint as to why neoadjuvant chemotherapy is the absolute right thing to do in the neoadjuvant fashion. Once we have those little presentations completed, we'll launch into a nice, friendly, lively discussion, and then wrap it up with some closing points.

So with that, Dr. Necchi, Take it away.

Andrea Necchi: Thank you, Ashish. Welcome everyone, again. So I would present, briefly, the data that we have collected so far regarding the role of immunotherapy given preoperatively before radical cystectomy in patients with muscle-invasive bladder cancer. You know and you will hear from Petros that there is a standard of care, which is presented by cisplatin-based chemotherapy. The administration of chemotherapy in this patient population has been complicated in the history of the treatment of this disease for many reasons because most of the patients presenting with muscle-invasive disease have also some problems in renal function that prevent them to receive any cisplatin-based chemotherapy. There is an additional proportion of patients who actually refuse to receive any chemotherapy before surgery. There are still some concerns regarding therapeutic treatments, the possibility to complete a full treatment course before surgery, and so on.

So actually the adherence to guidelines, the recommended use of cisplatin chemotherapy in these patients is still poor. And it's about 20, 30% of the patient population in total are receiving any kind of chemotherapy before radical cystectomy. Things are improving, but we are still navigating across these numbers in the United States, as well as in Europe. Since two years ago, we started, as many other investigators, dealing with the use of immunotherapy as a single agent therapy, a single therapy in some patients selected in one case or selected in another case before radical cystectomy. We investigated, for example, pembrolizumab in the Pure-01 study. In the PURE-01 study. The problem was to administer three courses of pembrolizumab in all-comers. So we hand-selected patients, irrespective of their renal function, irrespective of the biomarker status before radical cystectomy, and that the endpoint of the study was pathology complete response.

In the ABACUS study, the design was similar, two courses of neoadjuvant atezolizumab, but in most selected patients, in patients selected that according to the inability or fitness for, to receive cisplatin-based chemotherapy. And these two first studies investigating checkpoint inhibitors in this setting actually provided the evidence that the treatment was safe and might lead to some important results in terms at least of pathologic complete response to where approximately 40% in the PURE-01, 30% in the ABACUS study. The very, very preliminary survival outcomes have been actually presented as interim data. This is one of the most important concerns regarding these studies. We still lack mature data on survival endpoints from both of these studies. And there is a big issue about max, we will deal in the next few slides, about the biomarkers.

And then we have additional studies that have been presented more recently, like the NABUCCO study, which investigated the sequence of ipilimumab, ipi/nivo, and nivolumab before radical cystectomy in far more advanced patients. So in patients who also presented with the lymph node involved disease, clinically lymph node-positive disease, and here again, there was a signal suggesting that the combination immunotherapy may provide good results, also in a bit more advanced patients, patients with a bit more advanced clinical stage. And then we have a plethora of combination therapy trials. The first two trials have been, are mentioned here in this slide, that the Hoosier Oncology Group tried with pembro and gem/cis, or pembro and gemcitabine alone before surgery in patients who were eligible or ineligible to receive cisplatin, the BLASST study, which has been presented this year at ASCO GU with the combination of nivolumab and standard chemotherapy. All of these studies actually presented important data in terms of pathologic responses, but still survival data pending from all of these studies.

Which information do we have so far regarding use at least of single-agent checkpoint inhibitors in the preoperative space? We know at least that its efficacy in the short term, in terms of responses, has been demonstrated. We know that the administration of atezolizumab and pembrolizumab is safe, and we presented that also regarding surgical safety of checkpoint inhibitor administration. And we have investigated the long-term new way of staging and restaging patients and evaluating response with checkpoint inhibitors in order to try to avoid as much as possible invasive disease, invasive assessment, and in the next future, in the next trials, also in selected patients avoid major surgery.

And there is most importantly, the big issue of biomarkers as said, so this slide actually presents a wrap up of the data that we have collected for the PURE-01 study. Point number one, the activity of a pembrolizumab and the primary data that had been published two years ago. Point number two, the population of patients who may benefit the most from pembrolizumab treatment that we demonstrated that also patients, for example, with additional variant histologies like squamous cell tumors may benefit at least equally from pembrolizumab use compared to pure urothelial carcinoma patients. The big issue over radiological restaging, radiological tumor response assessment, which is still something that is a matter of clinical and the research debate, and it's an objective of clinical research in testing research, at least in my center. And the surgical safety, which is something that is very important because we are dealing with the multidisciplinary treatment, and we are dealing with strict collaboration with urologists in this very short and limited space for administering something like systemic therapies before local therapy.

We have also already a plethora of more advanced stage trials, randomized Phase III trials that are investigating the role of immunotherapy compared to the standard of care chemotherapy in these patients, in patients with muscle-invasive node-negative disease, of course. So you can see here some of the most important Phase III studies, they may provide a new standard of care in the next future. And we have also initial trials, initial trial designs that are envisioning a future for non-immunotherapy compounds or non-immunotherapy compounds combined with immunotherapy. And most importantly, ADC like in enfortumab vedotin looking to be combined with immunotherapy. Also, in this space based on the outstanding data that have been presented in metastatic disease.

So in conclusion, there is still an issue regarding the long-term activity and the efficacy of providing short courses of neoadjuvant immunotherapy before radical cystectomy in these patients. But of course, the data that we have so far regarding the proportion of patients who may achieve a pT0 response with single-agent immunotherapy is very promising, but there is a desperate need for biomarkers. We presented the initial data from the PURE-01 study providing that molecular subtyping may provide some important information, for example, indicating basal type tumors or [inaudible] tumors, meaning the tumor subtypes with the highest immune gene signature may benefit the most from immunotherapy use at least as a single agent, but it's still a big objective of clinical research, and we will have additional data, fresh data in a few days from the ASCO Virtual Meeting from new studies, combining immunotherapy with other compounds. And we're seeing the next future, which will be the role of immunotherapy, at least as a single agent therapy pending the results, of course, of a confirmatory Phase III trials that are ongoing.

So at least in my view, one of the most important objectives had been already been met, been reached, which is the rising enthusiasm of the patients and investigators in this field, in the field of muscle-invasive bladder cancer. So pending the clinical efficacy data, at least one major goal of immunotherapy in this context has been achieved. Thank you.

Ashish Kamat: Great. Thank you so much, Dr. Grivas, if you want to now tell us why you think that neoadjuvant chemotherapy still should be the standard of care in this patient population.

Petros Grivas: Thank you so much, Ashish, and I want to congratulate Dr. Necchi for not only his great talk today but also his very important contributions in the field in immunotherapy and bladder cancer and beyond. So excellent work. I'll try to show you some slides here, so to convince you and the audience that, until we get to where Dr. Necchi is trying to take us with immunotherapy utilization, the future for now, for the current time point, I think what we need is a practical implementation of neoadjuvant cisplatin-based chemotherapy, which is I think the standard of care and should be followed in patients who have muscle-invasive bladder cancer with resectable disease before radical cystectomy lymph node dissection. And basically with patients with clinical T2, T3 T4a disease, and when we talk about neoadjuvant chemotherapy, the term includes patients who have clinical node-negative, but in clinical practice, I think some of those practices may actually expand any group of patients with a single perivesical node N1 disease, which is a long debate about the node-positive patients. But I think the concept of today's focus discussion in the neoadjuvant therapy setting and for muscle-invasive localized resectable node-negative disease.

On my slides here, these are my disclosures in the last year. And here I would start by saying that the most important reason that we deliver neoadjuvant chemotherapy is to try to eradicate microscopic metastases, which the most important risk factor. And I think that's something we need to be aware of when we discuss with our patients, why we give the neoadjuvant chemotherapy. And that's a question with neoadjuvant immunotherapy as well, can immunotherapy eradicate micrometastases? Again, which is the strongest reason and rationale, why we give neoadjuvant therapy before radical cystectomy, trying to optimize outcomes by eradicating whatever might cause the demise of the patient which is metastasis and that's why we do it before the surgery.

The other reason is to try to downstate the bladder tumor and make the life of our surgeons, our colleagues in urological oncology easier, and that's why we will try to translate to have pathologic downstaging and pathologic complete response rates that with neoadjuvant chemotherapy, these can translate to better outcomes, longer overall survival. And we do not know as of yet, whether pathological complete response with neoadjuvant immunotherapy translates to longer overall survival, as Andrea mentioned, this is something that we need to evaluate with longer follow-up, whether the pathologic complete response rate translates to longer recondition overall survival, maybe with neoadjuvant immunotherapy, he made a good point. Patients do not need to recover after radical cystectomy if you were to give neoadjuvant chemotherapy as opposed to adjuvant.

And there's also the opportunity to assess the biology of the tumor real-time and see what is the behavior and response to neoadjuvant cisplatin-based chemotherapy that has prognostic implications. And I would argue treatment implications down the road. If someone has a platinum-resistant disease, specifically cisplatin-resistant disease, and you see no response to neoadjuvant chemotherapy, a pathologic resistant cystectomy, there is no point giving more cisplatin, platinum chemotherapy as the next step of therapy. You may switch at that point if the patient develops metastatic disease to immunotherapies and other therapies. There is also the opportunity of interrogating biomarkers, tumor tissue, blood, urine, and stool, and Andrea did a good job, a great job, both in his studies, as well as Dr. Dale, outlining the potential of that research. And of course, it goes without saying that we are working with evidence-based medicine, and there is clear Level I evidence support by randomized large Phase II trials and the meta-analysis, and all the guidelines support the use of neoadjuvant cisplatin-based combination chemotherapy, for those who can tolerate it and that are fit to receive it in localized muscle-invasive disease.

Where is the evidence coming from? As I mentioned, there has been a meta-analysis with approximately 2,700 patients. And this meta-analysis used cisplatin-based combination chemotherapy plus local therapy, VEGF local therapy alone. And in this particular study, meta-analysis particularly, there was a clearly demonstrated statistically significant benefit with overall survival benefit with cisplatin-based chemotherapy that pretty much recapitulated what was shown to randomized Phase III trials. And this was also corroborated by a low recurrence rate for these patients with statistically significant hazard ratios. Even in individual Phase III trials, we all know this SWOG 8710 trial led by Dr. Bart Grossman, who's a colleague of Dr. Kamat at MD Anderson Cancer Center. He actually led this large study with neoadjuvant MVAC, with older or concessional or classic MVAC. Before we have suites, nowadays, it's dose-dense MVAC. In this study, the classical MVAC was given, but radical cystectomy alone and [inaudible] plus overall survival, and that it was a significant, statistically and clinically you could argue, overall survival benefit with a median rate of survival, 77 versus 46 months.

And there was also significant improvement in the pathologic complete response rates, 38% with chemotherapy followed by cystectomy. That's 15% with cystectomy alone. And with neoadjuvant chemotherapy, it seems that the higher pathologic complete response rate, the longer overall survival. And I think that link is important to try to validate even further and try to see whether this is also true in the neoadjuvant immunotherapy studies, and with longer follow up, we'll be able to answer this question as Dr. Necchi mentioned.

The other important Phase III trial, in addition to the American SWOG 8710 trial was the EORTC European trial, similar design, about a thousand patients, bigger study, no doubt. And this study had three cycles of CMV, which is pretty MVAC minus Adriamycin®, which has no neoadjuvant chemotherapy followed by radical cystectomy or definitive radiation. That was one of the differences compared to the SWOG 8710 study.

And in this particular study, there was a similar result, pathologic complete response rate with neoadjuvant chemotherapy was about 33%, and that was a statistically and clinically important, significant improvement in overall survival with the use of neoadjuvant chemotherapy before local therapy versus local therapy alone. And I think in both studies, the neoadjuvant chemotherapy was feasible, did not result in any compromising of the base during surgery and did not significantly delay the surgery. So I think that's an important point that it's safe to give neoadjuvant chemotherapy. And I have to make the point that these regiments of the classical [inaudible] MVAC have evolved, and nowadays we use either dose-dense MVAC are shown in studies by Dr. Choueiri, [inaudible] and Dr. Flaig, or gemcitabine cisplatin, which is commonly used on a three-week cycle in the neoadjuvant setting based on some Phase II data and extrapolation based on other studies. So this dose-dense MVAC and cisplatin have less toxicity compared to the older classical commercial MVAC.

I just want to spend a few seconds discussing who is eligible, fit for cisplatin. I think we follow, like I did develop from Matt Galsky and colleagues of 2011, ECOG PS of 0-1, creatinine clearance of 60 cc or more, however, many of us feel comfortable going down to creatinine clearance of 50 cc per minute or higher. Some people go even lower, go to 40 or higher, and this debate and how comfortable people feel with different cutoffs of creatinine clearance. And nephrectomy tubes can be used to relieve the obstruction, and this actually can improve creatinine clearance and increase the pool of patients who can safely get neoadjuvant cisplatin-based chemotherapy. You have to keep that in mind. And there is also this notion of potential getting split-dose cisplatin for those patients with borderline creatinine clearance, specifically those between 50 and 60 cc per ml clearance for the cisplatin dose, and there have been some small data sets looking at the split-dose cisplatin. Of course, the level of evidence is not very high with this approach, but it's used frequently in clinic.

The other consideration is options of high-grade hearing loss of peripheral neuropathy or significant heart failure. These are factors we take into account when we make decisions about fitness or eligibility for neoadjuvant cisplatin-based chemotherapy in clinical practice. The important point to also make is that we should be careful and do not use carboplatin in the neoadjuvant or adjuvant setting in localized resectable muscle-invasive bladder cancer, because the level of evidence is not as high as with cisplatin, and there's no proven overall survival benefit with carboplatin neoadjuvantly. There's also concern about potential lower blood counts delaying cystectomy. So if someone cannot get cisplatin, I think the options are clinical trials or [inaudible] radical lymph node dissection, or in some selected patients, bladder preservation could be considered based on criteria. And usually, we use four cycles of dose-dense MVAC or gemcitabine cisplatin for the neoadjuvant cisplatin-based chemotherapy. And this is specifically for those patients with node-negative scans.

Takehome points, disease-free and overall survival has been demonstrated and is Level I evidence with cisplatin-based combination chemotherapy, no studying chemotherapy has no proven role so far in the neoadjuvant setting. I mentioned to you that we have evolved from the older conventional classic MVAC, the dose-dense MVAC, and many providers are using cisplatin on a three-week cycle. As I mentioned, there has been the SWOG 1314 trial by Dr. Flaig, presented at SUO of 2019, we have not seen the manuscript yet in this trial, the COXEN trial was not powered to compare the two regimens, dose-dense MVAC and the cisplatin, but indirectly showed compatible pathologic complete response rate in this neoadjuvant setting, and again, not [inaudible] onto this question, but relevant data. And, of course, as Andrea did a fantastic job, there's very, very interesting emerging data and where the field is going in the future with neoadjuvant immunotherapy trials, either single agents or combinations as he showed, and also huge work with biomarkers in the fields that Andre and others have done great work on it.

I mentioned that the multiple trials, I think Andrea already mentioned many of those, so I will not go over, but I want to point out that a significant opportunity for biomarker development and validation with all these studies. And I think the data is very promising. I agree with Andrea on that, but until we get there, we have to conclude Phase III trials in [inaudible] clinical trials to generate the needed level of evidence before we can practice. So before we go there, I think we'll have to stick with a Level I evidence with neoadjuvant cisplatin-based chemotherapy in those that are fit enough to get it. Thank you so much for the opportunity today and great discussion and to see both of you.

Ashish Kamat: That was perfect. And both of you cover a lot of information in your slides. In the interest of time, obviously I have to limit our time, so let me actually flip it over and ask you a question, Andrea, if you had to say three main criticisms against considering immunotherapy in the neoadjuvant paradigm, what would those be?

Andrea Necchi: Yeah, I would say, as I said, the lack of long-term data, which is the most important limitation of the data that we have collected so far. So event-free survival and overall survival data are of paramount importance here, much more, I would say than a pathologic response, also because of there may be a different relationship between pathologic response and survival with the use of immunotherapy compared to what we have seen with the use of a standard cisplatin chemotherapy. The second point that I will mention is that we still lack the right information regarding the optimal sequence, the optimal duration of immunotherapy. We don't know if three courses of neoadjuvant immunotherapy are sufficient to provide the patient with the cure combined with the radical cystectomy, or if the patients may require some additional immunotherapy and then the adjuvant phase like it is being provided by most of the studies, the big studies that are ongoing and are recruiting patients so far.

And finally, the role of biomarkers. We have published recently in European Neurology, the biomarker data related to the RNA expression data, subtyping data in relation to the activity of immunotherapy providing, for example, that patient with the basal subtype tumor or [inaudible] meaning basal supplied with the highest immune gene scores may benefit exceptionally long-term with the use of immunotherapy. But what about the rest of the patients? So also dealing with the use of single neoadjuvant immunotherapy, and even more complicated with combination immunotherapy, we actually will need to select more finally the patient at least for a single agent immunotherapy approach.

Ashish Kamat: Yeah. Excellent points. Because you know, sometimes we'll hear people criticize the use of immunotherapy in the neoadjuvant fashion based exactly on what you said, the long-term data. We don't know the long-term data. The subtyping is interesting because your data suggests that the basal subtype might respond better. There are other data from IMVigor, for example, that suggested a luminol might respond better. Let me ask you one question there because I also know that your analysis suggests that the FGFR3 positive patients would not necessarily be those that you would say don't respond to immunotherapy, but there is conflicting data. So can you comment on that a little bit?

Andrea Necchi: Yeah. As you said, it's conflicting, because if we merge the data that we have in the metastatic setting and the early data that we have in the early-stage setting, the most important information that we have got so far is that there is no reason in both early-stage bladder cancer and in advanced stage bladder cancer to exclude the patients from immunotherapy option, even though there are tumors or any kind of FGF receptor alteration, mutation, or fusion. But there is still something that requires additional research because as you mentioned, the FGF receptor 3 alteration now linked or reached in the luminal type tumors. And these tumors are features that are also associated with the resistance to immunotherapy. So according to the data that we have so far, we cannot exclude patients from immunotherapy, but we still need some more research.

Ashish Kamat: Great. And then Petros, to wrap up. If I had to ask you, what are some of the reasons that you would not use chemo in the neoadjuvant setting?

Petros Grivas: I think I see that silence lies, that many patients are not fit for cisplatin for the reasons I mentioned in my talk mainly because of kidney function. I think that there is probably some attempt in academic centers to try to use more cisplatin just because we know that's the best drug we have. And that's where the level of evidence is. But still, I think a significant proportion of patients may not be fit enough to get cisplatin. And these cisplatin-ineligible patients have been great prototypes or examples for clinical trials with immunotherapy early on. But as Andrea mentioned now, we'll try to expand and evaluate immunotherapy, even in patients with cisplatin fitness as I call it, with patients who are fit to get cisplatin. I think the other challenge is potential toxicity. And if you have a patient who you're very worried about, because a lot of medical mobilities are beyond the [inaudible] criteria, very severe COPD, on oxygen use. This potentially could affect the performance status, but low nutritional status with significant weakness there, or other reasons, social support, ability to come to get the neoadjuvant therapy in the cancer center.

All these factors are taken into account, and I think as oncologists, we try to objectify, if I can use this verb, try to make more objective our patient selection and the criteria, because sometimes we rely on the [inaudible] criteria, which are great, and also the eyeball test as I call it to see if someone is fit enough for cisplatin. So I think, there are other parameters to look at, sarcopenia, and other clinical factors that can help us make those decisions. But for now, I think we rely on the [inaudible] criteria, the eyeball test, as I mentioned, but patient selection, I think is one of the challenges in neoadjuvant chemotherapy.

And the last point is biomarkers. I think Andrea made this point for the neoadjuvant immunotherapy. We're still struggling, 20 or 30 years later to validate clinical useful biomarkers for cisplatin-based chemotherapy in bladder cancer. There are some very interesting and promising data with the DNA damage response to mutations. For example, Dr. [inaudible] has done work with the ATM RB-1, function C gene, Dr. Rosenberg and [inaudible] with two inactivating mutations. And we have originally seen data from the COXEN score that did not pan out to be clinically useful in the COXEN trial by Dr. Flaig. So some of those DNA repair gene mutations that I mentioned before are being tested. There are three prospective clinical trials looking at this, and I think it will be important to follow those trials. But I think the COXEN trial for gene expression profiling, reminded us how difficult it is when it comes to the final validation step to validate those biomarkers, as Andrea mentioned, but we remain resilient and we keep doing research to try to improve the field and the outcome for those patients.

And hopefully, in the future, we might be able to select which patients can benefit from which treatment and have the right patient, right treatment, at the right time, potentially combining chemotherapy or immunotherapy. There are Phase III trials doing this assessment combination of immunotherapy and ultimately we'll have a better way to select our patients.

Ashish Kamat: Great. Excellent points, both of you. I could go on forever just listening to you guys talk, every time I hear you guys speak, I learn a lot, but in the interest of time, we will wrap up now. Once again, thank you so much for taking the time to join us today. Stay safe and stay well.

Petros Grivas: Thank you so much.

Andrea Necchi: Thank you so much. Thank you.