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Andrea Necchi: So, welcome. Many patients are still following us by YouTube, and this meeting is primarily dedicated to them. And when focusing on clinical trials and when focusing on the advances in clinical research in disease such bladder cancer, you will see how the life changes, and then, the patient life has changed substantially in these last 10 years.

When thinking about how to deal with, in my presentation, I think that the best way to summarize the recent past in the development of bladder cancer therapy was focused on... Was by focusing on the people that dedicated their career and made huge advances in the bladder cancer, and then focusing on clinical trials that have been conducted by these people.

This is my disclosure. Of course, we as oncologists are putting the roots back to the old times of BCG therapy in bladder cancer. So we are focusing on the last 10 years, and we will focus on the last 10 years of clinical research, but as a matter of fact, we should don't forget the fact that we are still very much close to the standard of care that was introduced quite before in urology. And we are still revitalizing this issue and this opportunity, in particular, for non-muscle invasive disease, and we'll see in the next few slides.

The occasion is good when dealing with the first advances on immunotherapy, on systemic immunotherapy, metastatic bladder cancer, to remember a giant in genitourinary oncology, Nick Vogelzang, who passed away recently. So please make an applause to him for his outstanding contribution in... And together with Tom Powles, we had a pleasure to have him a few weeks ago in San Raffaele.

They presented, for the first time, the primary results of the phase 1 study that included patients with bladder cancer, providing the first hint, the first evidence that we may provide some substantial changes in tumor dimension, in tumor metastasis, by looking at the PD-L1, the PD-1 targeting in these patient. This was the first major step in the recent story of immunotherapy in bladder cancer.

Following this phase 1 study, another phase 2 study with atezolizumab monotherapy in patients with advanced urothelial cancer, later line chemotherapy treated, many lines of therapy. And these two guys, Jon Rosenberg from Memorial Sloan Kettering and Robert Dreicer were the first and senior author of a pivotal study of, it was called the IMvigor-210, which was the first phase 2 study to provide the evidence of activity of a single adjunct atezolizumab being for advanced bladder cancer. And based on this, atezolizumab was granted accelerated approval in bladder cancer by the FDA.

More mature data followed this phase 2 study. And the third pillar in the story of the immunotherapy development was the first phase 2 study to provide a significant advantage compared to standard chemotherapy in patient in second-line, third-line bladder cancer, Joaquim Bellmunt and Dean Bajorin were the first and last author of this pillar published in New England Journal of Medicine, the Keynote-045, which was a randomized phase 3 study comparing pembro with standard of care chemotherapy and providing a new standard of care in Europe as well as in United States and worldwide.

Following these first two pillars, of course a myriad of other trials provided evidence of new drugs, a lot of new immunotherapies, new compounds, targeted therapy, ADC. We'll go through the major steps in the next few slides, but just to summarize the fact that there has been an explosion since 2016 onwards in registration of new drugs both from the European side and from the United States side. And you can realize very easily that since 2016, life has changed substantially for, and opportunity have changed substantially for, bladder cancer patients throughout the clinical stages.

What is the most significant advantage? Improvement, in my view, may come when looking at the long-term data from these studies. And these are long-term studies from people who study with the nivolumab and with the chemo Keynote-045, looking at the long-term maintained remission of these patient, meaning that also when dealing with patient with the far-advanced disease, we could provide the cure for is proportion of these patient.

Metastatic disease, this is not something new in geooncology because you should go back to the initial experience with the high-dose IL-2 with Steve Rosenberg United States providing evidence that we could cure some patient diagnosed with advanced renal cell cancer.

Here is the same with checkpoint inhibitors. We can cure a small proportion of patient at long term. So that was something that was incredibly unexpected until quite recently. At the same time, we struggled against the first issues against the first limitation of the drug development in this disease because when we tried to combine immunotherapy with chemotherapy, we did not realize that we may be successful the same way. And these are the three phase 3 studies that provided results so far trying to combine immunotherapy, checkpoint inhibitors with standard chemotherapy, and comparing the combination with standard chemotherapy. And these trials fail to meet the primary endpoint of improving PFS, improving overall survival.

Things are changed when we dealt with another different strategy, which was not to combine drugs but to use them as sequence. To use chemotherapy first and then immunotherapy as a booster for responders. And this strategy changed substantially the situation. The other struggle was against the biomarker. We are still waiting for the ideal biomarker. We will hear from Jeff Ross and the huge amount of work that has been done in terms of biomarkers by pharma and by colleagues, by academia. But we are still far from the identification of a suitable biomarker to use in real-world practice to select patient who may be the right candidate for checkpoint inhibition, in particular when dealing with combination therapies.

Again, long-term data in this case from phase 2 entry studies in first-line long-term follow-up data. Again, you can see here that we are dealing with metastatic bladder cancer, and you see the survival curves provided the long-term from these studies, meaning that also in these cases, also in these studies, a few patients could be cured with checkpoint inhibition as monotherapy.

We have the pleasure to have today one guy at under 40 was the senior author of another pillar in bladder cancer story. Published in New England Journal of Medicine, the JAVELIN 100, which was the maintenance strategy as I mentioned, chemotherapy followed by maintenance of avelumab responders. Randomized phase 3 study, avelumab compared to best supportive care, providing statistically-significant clinically-meaningful improvement in PFS, in OS response rate, quality of life, a lot of other endpoints. So another major step was in first-line with sequential therapy rather than combination therapy.

And these are the data long-term, providing a substantial rise in couple of markers for survival, for PFS, and overall survival.

Then we also focused and we also have a huge advance in a different approach in these patient, which is a biomarker approach. And we have today the pleasure to have another author of another pillar in this disease, Yohann Loriot was the first author of the erdafitinib phase 2 study. Erdafitinib was and is a targeted therapy against the FGF receptor genomic alteration in bladder cancer that are found in about 15%, 20% of advanced bladder cancers. And this is the first targeted therapy to be recognized as standard of care, in the United States at least, in bladder cancer patients. So another major pillar that was provided by academia-industry partnership.

And these are the PFS and overall survival curves from these patient treated. Already treated with chemotherapy, some with immunotherapy, failing immunotherapy, and then receiving and benefiting from targeted therapy at this time.

The following point was how to best combine immunotherapy with the partner? Because we mentioned the fact that we failed to combine chemotherapy at least based on the data so far, but is there a better partner compared to chemotherapy to combine with immunotherapy? The answer is likely yes. These two guys, Jon Rosenberg from Memorial Sloan Kettering and Dan Petrylak, were the first and senior author of other important studies, phase 2 and phase 3 studies. The EV-201, EV-301, which tested enfortumab vedotin, an antibody drug conjugate targeting a protein which is called Nectin-4, in patient with advanced disease, providing again another standard of care in patient already treated with chemotherapy and immunotherapy. So another option for these patient that is a standard of care today in United States, in Europe, and in many other geographical areas.

And this is the fresh data presented at ESMO with a combination of EV and immunotherapy. And we realize that by combining in EV and pembro, for example in first-line patient who are naive of chemotherapy, of any treatment, we provided overall ORR response rate that was outstanding, 65%. That was unbelievable until quite recently. Unbelievable. And we will see if the data will be confirmed long-term with further studies.

And then we go to early stages because, as Professor Montorsi has mentioned, we started in 2018 testing immunotherapy as a way of treating patients before cystectomy with just a few courses of immunotherapy. This was, I would say, primarily an educational journey, an educational opportunity for young people to invest their career on this type of model, on this type of approach of treatment. And I think here there are many, many young guys, many young investigators, and I deeply suggest them to invest their career in disease model like this one that are very well-suited for doing clinical research, translational research, because you may have a lot of biomarker to enrich the clinical outcome data.

And following the PURE-01, a lot of other studies have been published with immunotherapy or similar strategies in the same clinical setting, providing evidence that we are still at the beginning of the journey. We are still far from a standard of care because the data are still jeopardize. We are in good shape, we are in the right way, but we are still far from setting a standard of care. Because there have been people that were smarter than us treating patient adjuvantly rather than neoadjuvantly. And in fact, the first checkpoint inhibitor to be set as an additional standard of care in early stage disease was nivolumab, thanks to the work led by Dean Bajorin and Matt Galsky, another major pillar in this disease, nivolumab as adjuvant therapy in high-risk disease after radical cystectomy or radical nephroureterectomy. Another tool in the therapeutic arena, operations with bladder cancer. And these are the survival curves for these patients.

Another way of looking at the same thing is to look at biomarker, and Tom Powles from the atezolizumab study, adjuvant study, quite similar to the nivolumab study, provided the data that ctDNA could be a very strong candidate for biomarker, create a strong candidate biomarker to use in these patient.

And because the ctDNA was prognostic, was predictive of immunotherapy benefit, the clearance of ctDNA during immunotherapy adjuvantly was prognostic in these patient. So a lot of major pillars collected from a phase 3 study with adjuvant atezolizumab, and we will see if the ctDNA will become a new biomarker to use, and we will have a lecture on this later today.

We shall move also even earlier in this disease, in non-muscle-invasive disease. This is actually the full revolution, the completion and the closure of the circle of the revolution in bladder cancer. Because thanks to people like the guy that is seated in front of this room, Ashish Kamat, Arjun Balar, Professor de Wit, they were the leaders of the KEYNOTE-057 study, pembrolizumab monotherapy in patient with non-muscle-invasive high-risk carcinoma in situ after failure of BCG. For the first time, medical oncology entered into the urology department, the surgical neurology department, meaning that we should reshape the entire way we treat patients even within hospital, and we should set things quite differently. Also in logistical terms, when treating patients with non-muscle-invasive disease with systemic therapy and potentially with intravesical therapy combined.

I would like to close the door with the point that is a very huge point. That is the natural consequence of such kind of revolution, short, quick revolution, major steps conducted and achieved in such a short time, because we are forgetting too many things far behind of us. And in particular, we have set and we have mentioned a lot of new therapies approved by FDA, approved by EMEA. But, as a matter of fact, these therapies are unavailable for the majority of people living worldwide. And the colored area are the area in which these new drugs are approved. And approved does not necessarily mean available because there are further issues of payment issues, reimbursement issues. Availability is something that is not the same of approval. So you can see here that the far majority of the geographical areas are still behind of us in clinical research in development, so we should take care of this when dealing with the next developments.

So I would like to close with this point. The first one is the point of safety. I have not mentioned anything regarding safety, but safety is of primary importance when dealing with new drugs. And we are struggling against new issues of safety, new safety signals that we, for the management, which we are still a bit unprepared. And particularly when dealing with new drugs in the early disease stage, the sequential at how to best integrate all these therapeutic caution together in sequence or in combination is still an issue.

Most people are still far behind of us, as I mentioned. So when looking at the next decade, I would focus on the fact that we are still to fill the gap that we have created in the therapeutic development in this past 10 years, looking how to best integrate the advances that we did by providing these advances to all people worldwide. And by improving the use integration of all these drugs altogether.

That said, I would like to thank you, and alight on the fact that all these achievements are usually a huge team effort. You cannot be successful in clinical research without a successful team. And I would like to thank, first of all, my clinical research team, the surgical team led by Professor Montorsi, the lab team, and the Urological Research Institute. All together we could make, and we will make, success as a team, and everything made is a team effort. Thank you.