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Ashish Kamat: Hello everyone. Welcome to Uro Today's Bladder Cancer Center of Excellence. I'm Ashish Kamat. I'm here at the AUA 2024 in San Antonio. And it's a pleasure to welcome to the forum a dear friend of the forum, a dear friend of mine, and an expert in bladder cancer, Professor Petros Grivas. Petros, welcome.

Petros Grivas: Fantastic to see you. It's great to be at AUA 2024. And what a great opportunity to be here during Bladder Cancer Awareness Month, which is May, that's why I'm wearing this bladder cancer T-shirt to raise awareness. Thank you for having me.

Ashish Kamat: That's a great T-shirt you have on, Petros. I thought it was because you lost your luggage coming here, but it's so appropriate and no, it's a great month to raise bladder cancer awareness. With that in mind and with the bladder cancer awareness, we all are aware of the fact that our patients who have invasive disease do not want to lose their bladder. So today, let's have a conversation about a topic that you're going to debate tomorrow at the IBCG AUA forum, but I'm not going to have you debate it today. I want you to share with our audience and with me, what are some of your views on where we are today, either with neoadjuvant chemo followed by X, or immuno followed by X? Where are we today when we can talk to patients about, hey, is it safe to save your bladder after the tumor has been treated?

Petros Grivas: It's a great discussion point, Ashish, and I think the field is evolving rapidly. So as you pointed out correctly, right now the standard of care has been in fit patients neoadjuvant perioperative cisplatin-based chemotherapy, followed by radical cystectomy and pelvic lymph node dissection or chemotherapy and radiation concurrently after a maximum TURBT and neoadjuvant chemotherapy could be a part of it. Bladder preservation are the two strategies we have to treat our patients with localized nonmetastatic bladder cancer.

So the question right now is can we see a future, shorter or further future, where we may forego local regional definitive therapy with radiation or surgery and we could potentially cure the patients with systemic therapy alone using effective and safe regimens and potential biomarkers to select the patients who may live long-term with great oncological outcomes. And that's what we're trying to do. And in a full disclaimer, we're not there yet today. I'm going to debate that tomorrow of course, but I think we're getting there. And how do we get there? Through innovative clinical trials.

As I mentioned before, surgery or radiation are needed for now for local regional definitive therapy. But there have been trials looking at strategies where systemic therapy alone in select patients may lead to long-term survival and great oncological outcomes. Which trials have been presented so far? We have the trial called RETAIN at Fox Chase with Dr. Plimack and Dr. Geynisman and that group. It was a very interesting trial looking at this question of how can you potentially cure patients with systemic chemotherapy alone?

They used dose-dense MVAC in that trial. They defined the potential therapy options at the time of completion of systemic neoadjuvant chemotherapy and they gave the option of bladder preservation to patients and they tried to look at two years, how many patients were metastasis-free. So metastasis-free survival at two years. They have put a benchmark, a metric for that two years, and they missed that metric just a little. So it was technically a negative trial, but it came very close and laid the principle, the foundation, that a select number of patients could potentially have great long-term outcomes with systemic chemotherapy alone.

In parallel, there was a very interesting, different but also important trial by Dr. Matt Galsky with the Hoosier Cancer Research Network Group that they used a combination of chemotherapy, gemcitabine and cisplatin, plus nivolumab, a checkpoint inhibitor. And that trial tried to define how we measure the clinical complete response rate, which is a challenge as we know after the completion of systemic therapy. So after the patients got gemcitabine/cisplatin plus nivolumab, they had evaluations with cystoscopies, biopsies, cytology, multi-parametric MRI, and CT of the chest. They tried to see if these patients had no evidence of cancer and they defined that as a clinical complete response if all of the above were negative. And they saw that 43% of patients achieved that endpoint of clinical complete response and that endpoint that if you achieve that state, you had a very high chance, extremely high chance to remain cancer-free or recurrence-free long term. So that trial was technically positive. And again, raised the promise, raised the enthusiasm, and the belief that some patients may do great long-term with systemic therapy alone.

As I mentioned before, we're not there yet. We need to validate these results with ongoing trials. And there are two of them going on, RETAIN II is a trial going on at Fox Chase, again, to follow up the RETAIN I. And there is a trial in the Alliance, the NCTN, the cooperative groups with Gopa Iyer and colleagues looking at a different approach with dose-dense gemcitabine/cisplatin chemotherapy. And they try to see again that question, if patients achieve clinical complete response, could they have long-term outcomes? So we're not there yet, but I think the data look increasingly promising. We just need more time, more trials and possibly biomarkers to select those patients. And maybe we can discuss biomarkers as well.

Ashish Kamat: Absolutely. No, in fact, I was going to segue into that anyways, but let me back up a little bit because you talked about the RETAIN study and you talked about Matt Galsky's trial and the clinical complete response. So when we see patients at our academic centers, and we use very focused ways to look at clinical complete response, CT, MRI, cystoscopy, biopsy, cytology. Over the years we've been, unfortunately, disappointed with the accuracy of the clinical complete response.

So if you take that clinical complete response, it's more a phenotypical reflection. In some ways, that's a biomarker itself of what's going on with the patient, how they responded to a certain treatment. And in the past, patients that, say, had neoadjuvant therapy and refused a radical cystectomy, many of these patients when they were followed long-term had recurrences, and they had invasive recurrences or even metastatic disease. So as a community, we've all been a little wary because we don't want our patients to lose their bladder, but we definitely don't want them to lose their lives.

So with that in mind, and all the work that you have done in the field of biomarkers, whether it's from metastatic disease, looking at circulating tumor DNA, urinary DNA, that's the next phase that we're coming to. So how do you foresee improving? First of all, tell me if you disagree with me, but I think we need to improve on what we have. Matt Galsky's results are great, but they're not perfect. So how do you foresee we can improve upon what we've already built?

Petros Grivas: That's a great point, Ashish. And as you pointed out, so far we have been challenged with how we measure, define, and then validate clinical complete response and what instruments we use to define that. And I think maybe a combination, a composite, let's say, definition with a negative urine cytology, negative cystoscopy, no tumor visualized, but also doing random biopsies in the absence of a tumor in the area where the tumor resection bed from the TURBT, try to resect that and make sure there's no tumor there. And of course, imaging. So imaging of the chest, abdomen, and pelvis. I think the MRI, which is a reasonable tool, especially with this VI-RADS system, can add some value in the definition of clinical complete response. Obviously, we need to make sure we have scalability and readers that can read the MRI across different centers reliably, reproducibly.

And I think the additional point is can we utilize, as you pointed out, additional biomarkers, for example, circulating tumor DNA. In the last five years or so, we have seen datasets looking at ctDNA as a potential prognostic biomarker. Data from Christensen et al in 2019 in Denmark showed that if you are ctDNA negative, meaning you have no detectable ctDNA before or after neoadjuvant chemotherapy, the prognosis is much better as opposed to patients with detectable ctDNA. We had the opportunity to publish in Nature with the IMvigor010 group, Tom Powles and others, and we validated that and we saw that after radical cystectomy, ctDNA-negative patients had a much lower chance of recurrence compared to ctDNA-positive patients. And that's a prognostic role. Of course, we try to evaluate that in other studies.

I think if you add the ctDNA biomarker to the conventional definition of clinical complete response and you add the MRI VI-RADS story, you may add more components and you might be able to better select those patients that actually may have great long-term outcomes because you need just more data points to complement the conventional definition of clinical complete response.

Now, the additional part of the story is molecular biomarkers, for example, mutations in different genes that may or may not predict response to neoadjuvant cisplatin-based chemotherapy or immunotherapy. The mutation that came closest to being a predictive biomarker but has not made it yet is ERCC2 mutations. That seems to enrich a patient population with a better response to cisplatin-based chemotherapy. We do not use ERCC2 in clinical practice yet, but it seems that those patients with those mutations may have a higher chance of achieving clinical complete response.

Dr. Galsky looked at that and his conclusion was if you achieve clinical complete response, it does not matter how you get there. Whether it is mutation-related or not, if you achieve a clinical complete response with that definition in his trial, this correlates well with long-term outcome. The addition of the mutation in this equation does not appear to improve that correlation of clinical complete response with long-term outcome.

So I think to summarize, we need experienced urologists, experienced imaging radiologist experts to synthesize the data points, do very good quality cystoscopy, maybe the blue light that you guys are using for higher sensitivity to pick up lesions. You know this better than I do. Maybe that may be a tool. MRI, biomarkers, and of course validation of those in prospective trials. And the last point I would say is better effective systemic therapies. We think about pembrolizumab/enfortumab that has revolutionized the metastatic disease setting. Right now in the front line, there are two ongoing phase three trials looking at pembrolizumab plus enfortumab. So if we think about more effective systemic therapies, the chance of achieving a clinical complete response is higher already. So with better systemic therapies and better imaging, better biomarkers, I'm hopeful in the future, we're not there yet, we're going to hopefully be able to cure more patients than now with systemic therapy alone.

Ashish Kamat: Petros, again, you gave a lot of information and there's a lot to unpack. I'm just going to tease out a few things for the benefit of our audience. So I'm glad you made the point and emphasized what Matt found in his trial. The clinical complete response is the best biomarker. No matter how you get there, because everything else sort of multiple pathways, but those pathways are relevant to whether the tumor disappears. And because of that, it's up to us, just like you said, to find out the best way to identify a true CCR from a false CCR, because that false CCR is what scares us about patients.

So I'm going to ask you a question about that in a second, but then that brings me to what's on everyone's mind, more effective systemic therapy. So we have EV/pembro in the metastatic phase. It's been looked at in the neoadjuvant phase. Now all the markers previously studied were based on DNA damage, cisplatin. Now we have immuno and targeted therapy. So will the field have to completely change all the markers they're looking at? What are your thoughts on that in brief? And then I'll go back to the CCR question.

Petros Grivas: That's a great point. And I think to your point, Ashish, so far pembrolizumab plus enfortumab has produced really, really amazing results in the metastatic disease front-line setting response rate, 68%, and the median overall survival approaching 32 months in the front line. However, we have not seen biomarker data from the clinical trials. We have seen some retrospective data from the UNITE study with Dr. Koshkin and others. But these data are, I would say, hypothesis-generating. So we need, to your point, more work in identifying and validating biomarkers that may help us predict the response to enfortumab.

There was a recent interesting paper by the European group looking at NECTIN4 gene amplification. It has been on social media with some comments about it. And that paper showed a high degree of correlation between NECTIN4 amplification and clinical response or radiologic response to enfortumab. I think we need to do more work in that domain. I think we can use the experience that we have had so far with evaluating DNA damage response genes like, as you said, ERCC2, other genes, utilize that experience, but also keep an open mind about the biomarker discovery and look, for example, at the target of EV like NECTIN4. Look at the payload MMAE. It's a microtubulin disruptor. Can we learn more about the mechanisms of response and resistance to this drug?

I think it will be very important and will serve us well down the road because it will also give us the opportunity to understand why patients may develop resistance to it, and also immunotherapy. So MSI high is an example. It's a very rare phenomenon to have microsatellite instability in bladder cancer. Very, very rare. It's less than 5%, but those patients may have an extreme response to inhibition. So I think as we get more data about genomic sequencing we'll get better, I think. And of course, having tissue before and after in the neoadjuvant setting, TURBT, cystectomy in patients who still get surgery, we are going to find out more and more about biomarkers in the future. We need more work in that domain.

Ashish Kamat: Absolutely, and I agree with you, and that's where we're doing research and people like you are leading the field. I'm going to circle back to the CCR and have you in closing provide advice educational-wise for the audience that's listening. So if someone has in your clinic a patient off trial, off study, that has gotten neoadjuvant chemotherapy, was planned to have, let's say, radical cystectomy, and comes back and says to you, and this is again in the clinic, no research questions here. Says, Dr. Grivas, I got chemotherapy. My bladder on imaging looks clear. I want to save my bladder. What's the advice today, May 2024, that you would give that patient based on everything you have available at your disposal today? And that's the closing message to our audience.

Petros Grivas: Great question. So research is very exciting, but today, if that patient comes to my clinical practice, I would strongly recommend and advise that patient to get definitive local regional therapy. If the patient has received neoadjuvant cisplatin-based chemotherapy and has already embarked on the journey of radical cystectomy and lymph node dissection, that's a very standard approach. And I would strongly recommend that. The alternative would be chemoradiation. And of course, we have a long debate about the utility of neoadjuvant chemotherapy before chemoradiation. I think it's reasonable, but may not be mandatory. There is variability in practice on the neoadjuvant chemo, but chemoradiation may be a great option for a patient who refuses cystectomy despite adequate counseling.

But I would definitely advise that patient to get either/or to have a definitive local regional approach because, to your point, we need more data, more sample size, more long follow-up, more validation to clarify and confirm the correlation between clinical complete response and long-term outcomes. We're not there yet. We're getting there, but that patient will need some form of local regional therapy, either radical surgery or radiation with concurrent chemotherapy. The question is, do you do another look in the bladder to see if there is any tumor to resect before concurrent chemoradiation? And that's the value of a multidisciplinary clinic in that context.

Ashish Kamat: And we'll have you back for another talk at another time for that discussion. But today, thank you, Petros, for taking the time. Thank you for coming to the AUA and enjoy the rest of San Antonio.

Petros Grivas: Thanks for having me. What a great meeting. Thank you.