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Ashish Kamat: Hello everybody and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center. Joining us from Milan is Professor Andrea Necchi, who has been on this forum multiple times for very important reasons. Today, Andrea, thank you so much for taking the time to join us and discuss with our audience, not just the consensus recommendations that came out of the San Raffaele meeting last year, which is very important, but also your thoughts in general about optimizing the use of next-gen sequencing in patients with urothelial carcinoma. Thank you again so much.

Andrea Necchi: Thank you, Ashish, and thanks to UroToday once again for the opportunity to provide you with my perspective on the topic. Yeah, as you mentioned, this topic is a cool topic for routine practice worldwide, I would say, and deeply involves patients diagnosed with urothelial cancer, among others. So I would go very briefly with the summary of the data that we have published from our consensus. It was conceived as a consensus panel recommendation within our second edition retreat meeting held in November last year in San Raffaele in Milan. So we decided to focus in particular on the issue of the need to optimize the use of NGS in patients with urothelial cancer. The methodology was quite easy. A modified Delphi consensus. The panel of experts were addressed 15 statements. They had to agree, disagree, or abstain in the first round. The statements in which we had disagreements were discussed during the meeting and then there was a further round, a third round after the meeting for final agreement. So I would like to focus on the next two slides on the issues and the statements that have been discussed.

I think that it is most important to focus on the statements rather than the results of the consensus because they may provide hints for today's discussion. You see in particular that there are multiple topics to consider when dealing with the issue of NGS indication in patients with urothelial cancer, not just focusing on the urothelial histology, but also including variant histology. There was an agreement on this. The focus on urothelial and upper tract urothelial cancer for sure, which is, as you know, enriched with FGF receptor alterations, so potentially, druggable alterations. But most importantly, dealing with the technical possibilities of providing different kinds of NGS assessments. We discussed the issue of liquid biopsy as to be preferred to tissue biopsy, and there was disagreement on this. So the tissue biopsy was still the main focus of our attention when considering these patients and the need for genetic counseling in patients who have any kind of potentially genomic alteration or potential germline nature. These are the topics on which we had the most disagreement.

One of the first topics has to do with the timing of the tumor biopsy in relation to the need for NGS assessment. For sure, as a general statement, as a general recommendation, it is always better to deal with recent tissue, although there is no agreement, there is no definition of what is defined as recent in this disease in this setting. But for sure, not using tissue that is very old or very outdated or tissue that is related to surgery, previous many that is anticipating many lines of therapy, for example, in patients with metastatic disease. The point of the clinical stage, not just focusing on advanced tumors, muscle invasive or advanced tumors, but also considering patients diagnosed with non-muscle invasive disease as potentially suitable for NGS assessment of the tumor. Because we do have today, trials of targeted therapy also in this clinical setting. So there is a possibility also for these patients to benefit from an NGS assessment.

For sure, the most critical point that has to do with geographical disparity is not to do with genetic germline testing or genomic testing itself, but the possibility of accessing targeted therapy that is associated with a certain genomic alteration. So this is a very critical point for sure. There is a huge disparity, as you well know, regarding access to novel therapies and to targeted therapies worldwide. So once the patient is diagnosed with a certain tumor harboring a certain druggable genomic alteration, actionable mutation, it is always difficult to find a way of accessing therapies. But this should not be an issue limiting the indication for genomic testing of the tumor of a patient. Instead, it may portend opportunities for the patients and for us as investigators to provide the ways for the patient to access clinical trials or access a way to administer the treatments. So these are very, very general. This is a very general overview of the points that we have discussed, and I'm very happy to discuss further with you, Ashish, with further topics.

Ashish Kamat: Thanks so much, Andrea. First of all, I want to compliment you because I think having a retreat like you have is phenomenal. I've been part of it and thank you so much for inviting me. But then having a deliverable like this that can come out of the meeting that you can then publish and educate people is even better, right? Because it helps inform others as to what people are thinking about, how they should be thinking about, and putting the agreement, disagreement lets people see that even amongst the experts, there's not 100% agreement. There are pros and cons of different things. So congratulations on this effort once again, and I look forward to being part of it again this year.

Andrea, if you could put on your hat as an expert, and now you're advising someone who's at a cancer center that's just coming up. Say it's just coming up, and it may be in a part of the world where they have access to NGS, but they don't really know the nuances of it. Could you, in short, putting on your hat as the expert advisor, advise them how to set up this whole NGS testing, what it involves, and how they can best implement it without straining their resources?

Andrea Necchi: So thank you, Ashish. It's a great question and has to do with the logistics or with the management of a certain cancer center or a unit or rather than the science. But I think that my two suggestions would be first to have good collaboration, external collaboration with external partners. My suggestion is to start with companies that have experience on pretty much focused on genomic testing. We had the pleasure since the very beginning of our retreat to collaborate, and we have the pleasure to have on the panel of experts, Jeff Ross from Foundation Medicine. It was really inspiring to me in the way we should find the potential for allowing patients to access and for us to access the genomic testing at the best of their potential. With not just the possibility of accessing the latest technology, but the possibility of collaborating with the people, physicians and the molecular scientists who were able to interpret the findings and to provide you with a clinically meaningful interpretation of the findings.

It is not something that is usually easy to find in local labs. The second point, in order to build in our facility, an infrastructure like this, is to rely on the collaboration with a smart molecular pathologist. I know that from many geographical regions, in many geographical regions, there is still a gap to fill in terms of educating the pathologist towards molecular pathology or scientists towards molecular pathology. So it is not easy to find the right connecting link between the clinic and the science in order to have someone who is able to interpret these topological findings and at the same time to provide you with a clinical interpretation of the genomic features. So my suggestion is like this, so looking outside first, collaborating first with third partners, and then trying to find out the right person, the right people to be in charge with this path.

Ashish Kamat: Yeah, I think that's an important message for anyone listening. It's a team effort. If you try to do it yourself, it doesn't work. Of course, you don't want to get all this information and then sit with the patient and not know what it means, right? Not everybody knows everything. So very good message there about collaborating and collaborating early on, seeking people that have the expertise if you don't have the expertise. Now, Andrea, of course, you have the expertise with NGS. So now, if I were to ask you this question that we get oftentimes, and we debate this too, what is the best time in the journey of a patient with bladder cancer?

Say they present with non-invasive and then they progress over time to hopefully never, but they do to muscle invasive and metastatic. What is the best time to start NGS? Is it the first time you see a patient in the clinic ever with a tumor? Or if it's a low-grade tumor, would you say, "Okay, let's just wait unless we have a clinical trial and only if it's high grade." What are some of the practical tips that came out of this retreat?

Andrea Necchi: Thank you. So very critical question. I'm not sure that there is actually an answer, but let's try to reason upon this. I think that for most of our patients, the patient that we are seeing, both of us are seeing in daily clinic, so patients who have been diagnosed with a non-muscle invasive tumor or muscle invasive tumor advanced disease, there could be an indication for genomic testing, meaning an indication for potential targeted therapy to use in their therapeutic path. So in principle, given that we do have clinical trials at least, or labeled current indications for the use of erdafitinib, for example, in advanced patients in the United States and hopefully in the near future in the European and the [inaudible 00:11:17] worldwide, there could be an opportunity to test the patient since the very beginning, so the first time you see the patients. On the other hand, there is a critical issue that was raised at the meeting by Neeraj Agarwal.

It was, I think, I totally agree with him in terms that there may be consideration to spend towards the utility of the patient's tissue and the fact that the tissue of the patient that is available from biopsy or from surgeries is not so huge to make us in the possibility of giving so many or in times the NGS testing. So we have to use very carefully the tissue. So in principle, I would say there should be for everyone the opportunity to test at the first time you see the patient, the tumor. But practically speaking, I think that there could be an indication to use the genomic testing and to rely on the genomic testing once you see there could be an opportunity for clinical trial inclusion or if a patient is exhausting the most important, the most effective standard therapy opportunities.

So at the moment, outside the clinical trial setting, we are still to be careful in using the tumor of the patients and saving it for the time when actually the patient would need outside of clinical trials for accessing new therapy. So the answer, I know that the answer is not so clear and maybe not so clear and needs translation in daily practice, but I think that is the test to do first with the trial availability first and outside of trial availability, standard therapy availability, exhausted which we should consider genomic testing.

Ashish Kamat: Yeah, I think if I would summarize, I think the key message there is do the genomic testing if it'll make a difference to what you are doing for your patient. Then that could be a clinical trial. It could be if you're looking at second line, third line therapy, and if you have sufficient tissue and say philanthropic support for research, then sure, you could do it otherwise. But we don't want to hurt the chances of the patient having a good pathology. So at our center, for example, the pathology department has to confirm that they have enough tissue to do standard of care testing beyond which we can use the tissue for NGS. I think that's something, like you said, we want to collaborate with our pathologist early on because the last thing you want to do is find out that, "Oh, we could not make a diagnosis of variant histology," and you want to go back and get some more tissue and the tissue's gone, right?

Because that clearly makes a difference if the patient has small cell neuroendocrine, things like that. Andrea, you and I could chat forever, but in closing, just one other question I want to ask you. Looking in the future, I know there was disagreement about which panel and liquid and ctDNA and all of those things, but looking in the future, where do you think? Let me just make it broader. Where do you think this whole testing realm is going to be next year?

Andrea Necchi: Well, I think that it depends on the clinical stage. For early-stage disease, meaning organ-confined disease, non-muscle invasive and muscle invasive disease, there is huge potential for urine tumor DNA, because here, when trying to address, for example, the definition, the proper definition of a complete response to certain therapies that may be intravesical therapies or systemic therapies, what is clearly the gap here and is also the gap for MRI, for example, on the various applications in the bladder, is the possibility to dissect or to identify the residual non-muscle invasive, high-risk disease in the bladder of the patients. So in this regard, I think that the urine tumor DNA assessment has good potential to clearly have a multifold definition of pathological or clinical complete response to a certain therapy for patients with advanced disease.

I'm pretty sure that the liquid biopsy in general will overcome the limitation of tissue biopsies and then the shortage of the tumor tissue available in most of the patients with solid tumors, including bladder cancer. So we had advances of technology for sure. Liquid biopsy, including the ctDNA assessment, has good potential for predictive prognosis and for identifying new targets for therapies for these patients.

Ashish Kamat: Absolutely. I think as technology improves, I mean, we've been doing this for a while. I mean, 20 years ago, you needed so much tissue. Now you can do it so much, and we're hoping we can just do it with liquid biopsies, which would be ideal. Then we could do serotesting without hurting the patient with repeated procedures and things like that. Andrea, once again, we could talk forever, but we do have to cut this off at a certain time. Thank you so much for taking the time and thank you to UroToday for allowing us this opportunity.

Andrea Necchi: It was a pleasure. Thank you very much.