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Sam Chang: Hi. I'm Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University. And I have the honor to really have one of the true leaders in the treatment of upper tract urothelial carcinoma for probably easily over a decade. Dr. Surena Matin is a full professor and attending at the MD Anderson Cancer Center. He really doesn't require any type of introduction. He has really led the way in terms of surgical techniques of different therapeutic interventions. He's here today to actually talk about a phase 1b trial that he has concluded with his colleagues at MD Anderson looking at actually the target of FGFR3 for upper tract urothelial carcinoma. So welcome and thanks so much for spending some time with us.

Surena Matin: Well, thanks so much for the invitation, Sam. Great pleasure to be here. And I'm excited to talk to you about this. Yeah. Terrific. So this is a study that we recently published in a Journal of Urology. It was a phase 1b trial evaluating the tolerability and activity of a targeted fibroblast growth factor receptor inhibition for localized upper tract urothelial cancer. You can see my co-authors there who were really critically helpful in being able to get this study accomplished. So FGFR3 activating mutations are very common in upper tract urothelial carcinoma. Anywhere from 54 to 92%. Definitely the higher incidence we see in low-grade tumors and compare that to what we see in bladder cancer based on the TCGA data, about 19% of bladder cancer. So really high prevalence of these activating mutations in upper tract disease.

Within upper tract urothelial carcinoma, we still have major areas of need. And there is a question about the role of FGFR inhibition in this setting. We have one approved drug, the mitomycin hydrogel. It's approved for low-volume, low-grade, upper tract urothelial cancer. There has been limited uptake by urologists because of concerns for ureteral strictures, although those are being mitigated over time with clinical experience. However, about 40% of patients won't respond to that. And if they do respond, another 40% will have a recurrence. And so we still have that to deal with. On the other hand, additionally, we don't really have good management for those who present with high-volume disease, and that remains a major problem still in regard to renal preservation in that setting. So FGFR inhibition is of course something that is approved for metastatic urothelial carcinoma when it's platinum refractory with some modest responses.

The question is can we use it earlier in the disease process when it's localized and have this be part of potentially a plan for renal preservation? Really, the first question is, can these patients even tolerate this drug? We've never given it to non-metastatic patients. And secondly, if we do give it, what kind of responses should we expect to get? Will they be clinically meaningful responses? And so these are the questions that we were interested in answering. And so as a result, it requires a phase 1b trial, meaning that we're using a drug in a population in which it has not been tested before. And based on power calculations, we were looking to enroll 20 patients. So we took patients with low-grade disease primarily. If they had high-grade, they had to meet low-risk criteria by nomogram or were ineligible for cisplatin therapy. They had to have a minimum baseline renal function with a GFR of 30 and enough tissue to do mutation profiling.

If they were eligible, then what we did was give them this drug, infigratinib. And one cycle was three weeks of drug and one week off, and then they took one more cycle of drug for three weeks and that was it. So two cycles or seven weeks of treatment total. And then we took them for whatever the planned surgery was based on what they presented with. And so the primary endpoint was tolerability. And part of this was a continuous safety monitoring plan. So for example, in the first five patients, if three of them were intolerant, then the trial would end. On the other hand, if most of them tolerated it, then it would go on to 10 patients and so on. And so as a secondary endpoint, what we of course were interested in was response rates. And what we did with this was model this in the same way that the registration trial for the mitomycin hydrogel was performed with tumor mapping.

Now, the tumor mapping at baseline was done after any biopsies or lasering that may have occurred. So all the residual tumor that was there was mapped, and then there was a mapping done again after the treatment and at the time of either ureteroscopy or nephroureterectomy. And so just to summarize the results of this trial, out of 14 patients, only two of the patients had to stop those two cycles because of adverse events. As I'll show you, one of the patients had a dramatic response even with just one cycle. These responses were dramatic and pretty rapid. Patients who did have the mutation had a six out of nine or 66.7% of them responded with a median 67% size reduction in their tumors. Three of these patients were planned on undergoing nephroureterectomy because of high-volume multifocal disease, and these were converted to endoscopic management as a result, including one patient with high-grade disease who only tolerated one cycle of treatment.

Patients who did not have the mutation did not respond. And that proof of principle I think we've established sufficiently and that we should not be expecting responses in those who don't have the mutation. Now, what had happened was that as this trial was ongoing, the drug manufacturer made a business decision internationally to pull their drug from the market, and all of the trials in oncology for this particular drug were stopped. And so enrollment ended at 14 patients. This is the waterfall plot that summarizes the results I just showed you. The black columns show those patients with FGFR3 alterations and the asterisks, those that were converted from initial planned nephroureterectomy to endoscopic management and including those with high-grade disease.

So these are the three patients that were converted. And I'll show you these examples. This is actually the first patient we enrolled. He had been to a couple of different academic centers, was intent on renal preservation. Every single center, including ours, recommended nephroureterectomy for this high-volume, low-grade tumor. And basically at that time, the trial was opened and the patient was interested in participating. You can see the pre-treatment retrograde, the CT scan. The ureteroscopy picture isn't great because we couldn't deflect down into the lower pole very well, but you just sort of see the tip of that tumor there. And then after two cycles of treatment, radiographically looked like a complete response. When we looked in, we saw this yellow hyaluronidase tissue, took some biopsies. The pathologist said it was treated papillary urothelial cancer. We weren't sure if this meant that it was viable or not. We considered it viable just to have higher standards of reference there. But overall, very dramatic. And the patient has done tremendously well since then.

This is the patient with high-grade tumor with low kidney function who only tolerated one treatment cycle. You can see this tumor filling the upper pole infundibulum and the calyces and endoscopic picture showing multifocal disease there. And then after treatment, basically we have a little bit of a nubbin of tumor left. And again, this is after only one cycle of treatment. And at this point, it was completely lasered. The patient was presented at our multidisciplinary conference because it was high-grade to begin with and elected recommendation as well as the patient's election was to continue with conservative management and continues to do well in that regard. And then lastly, this is the third patient who presented with high-volume disease in the right upper pole of the kidney. And here in the endoscopic picture basically shows the tumor poking through the infundibulum with that calyx being full of tumor. And then after treatment, it's almost gone except for this little bit of residual tumor that we were able to readily laser ablate.

So the take-home message with all of this is that FGFR inhibition appears to be very well tolerated. It's rapidly efficacious, possibly as a preoperative treatment for upper tract urothelial cancer. We may be able to use this as a strategy to convert high-volume or highly multifocal disease that we think is deemed for nephroureterectomy, but converted to renal preservation. It doesn't matter how much volume disease is there, unlike every other treatment strategy that we have currently available. The data for low-grade and high-grade disease is not really sufficient. We do need further study because we only had three patients with high-grade disease, but at least there is a promising signal that this may be relevant for some patients with high-grade disease as well. We also didn't have enough patients with lower levels of kidney function. Clearly this is a major area of need, and this is something that, again, we have a promising signal, but we need more data for.

In addition, these compounds are also orally available. And historically, urologists have shown great acceptance for oral treatments for their patients. While it's something that we currently are doing in collaboration with medical oncology as we learn more, potentially it's something that urologists could do. With this data, we are designing a phase two trial. There are multiple other compounds available now. Some are actually approved for cholangiocarcinoma. And we are having conversations with them about supporting this phase two trial. And the goal there would be to try to look at renal preservation. Thank you.

Sam Chang: Surena, when looking at this data, I'm ... Obviously everybody picks the best pictures, but I am struck with the fact that there were multiple patients with minimal treatment that would have such a dramatic response to high-volume disease. Tell me what you think is the most promising aspect of FGFR3 as a target. That it's so highly prevalent in upper tract disease or is it the fact that we may be equally efficacious with low-grade and high-grade disease? Is it the fact that we can be actually quite certain that we're not going to have any other targeted downstream effects? What makes FGFR3 such an attractive target? Because I think probably all the above really contributed to it, but what do you make it most exciting for you?

Surena Matin: Yeah. Look, I think it's all of the above, but I think the one thing that data really helps hone in on is that if you're going to have a response, it's going to happen pretty quickly. And in talking to those who are very active in this field, there's actually, believe it or not, an entire affinity group of scientists and clinicians revolving around FGFR3 treatment. I was recently invited to join them. And I'm really excited to be able to learn more from them. But that's what they're saying, is that, yeah, if a tumor is going to respond to this inhibition, usually it happens pretty quickly. Very relevant for our population because, look, it's an oral compound, but it still has side effects. And while we didn't have anything severe or permanent, the fact is that there is a high frequency of a lot of low-level side effects. So it's hard to ask patients with localized disease to be on these kinds of treatments for months on end. And so the promising thing here is that it can be a very short-term intervention for potentially high gain where we may be able to use that as part of a strategy, right?

Sam Chang: Right.

Surena Matin: It's a bit of a paradigm.

Sam Chang: You get that signal early on, just like you said of, is this is going to work or it's not? And if it's not, we're going to ... I hate to use the word [inaudible 00:13:16], but we're not going to just keep on giving it, waiting for that response. How does this differ then from ... Obviously we've looked at it in the THOR trials of oral erdafitinib for non-muscle-invasive disease. Basically the take-home messages from a urology standpoint were, "Hey, it may be effective, but the side effects were so great." This seemed to be better tolerated. Is that the agent? Is it the patient characteristics? Tell me a little bit about what in terms of differences between the two.

Surena Matin: Well, listen, I can't speak super eloquently about all of the compounds. You speak to each individual manufacturer and they're going to talk up their particular agent. Probably some of the newer ones, they undergo a lot of these design changes to, number one, try to avoid one of the most common causes of non-response with gatekeeper mutations or one of the things, the main things they look at, the side effect profiles and things like that. So that could be part of it. And there are some of the newer generation ones that are in the market, potentially may have some of those advantages. There's going to be some differences in trial design that also may have been a factor. Also, but I think when we try to translate the bladder to the upper tract, you also have to keep in mind the morbidity of upper tract management is a little bit more intensive than it is with a TUR. TUR sets such a high bar for anything else.

Sam Chang: No. Absolutely. Yeah.

Surena Matin: When we're looking at ureteroscopic management, that bar is a little bit lower. We're so limited in terms of what we can do and patients really don't love it when they don't love the stent either and all those things. So I think all of that contributes. Now, with some of the newer generation drugs that we're looking at, there is promise for those to be a little bit better tolerated potentially. But I think also when you're telling patients, "Look, this is really just short term." There may be a mental aspect of that where they're willing to maybe put up with it knowing that there's a very finite limit to that.

Sam Chang: So last question. Where to next? Obviously this target is promising. It has garnered great interest in multiple different types of malignancy types. Will it be other agents, other focusing on a high-grade disease? Where to next because obviously you've made some great inroads in terms of, hey, we've got some promising things that we have available that may help obviate the need for nephroureterectomy and be able to preserve. What next for you and the folks at MD Anderson?

Surena Matin: Do you mean specifically for this intervention necessarily?

Sam Chang: Yeah.

Surena Matin: Yeah. I think what I really would like to do is have ... We need a larger trial. I think we need more data. The focus I think will need to be on low grade. I think once we start introducing high grade, it starts getting much more difficult to combine them especially. But there's definitely an area of need for high grade. I think including those with lower ... less kidney function is going to be really important. Those are our most challenging patients, right? Challenging patients. Managing those with GFR of 70, 80, 90 is a bit of a no-brainer. You can really pick your poison with that pretty easily. But when you're getting down to the 30s and 40s, that's of course the more common patient and they're so ignored in all our clinical trials.

In fact, for this phase one, it took a lot of conversation with the manufacturer to agree to get patient, to enroll patients with GFRs of 30 to 45. We had to add a lot more testing and monitoring for those patients. And so I want to keep doing that to make sure that we advocate for our patients who really are much more vulnerable in that situation. We just need to build in sufficient safety parameters to be able to show that you can do this. But again, it's such a short-term intervention that whatever adverse events they get, almost all of them are reversed fairly quickly once they discontinue the drug.

Sam Chang: Yeah. No. I think we all owe you and your co-researchers really a tremendous set ... a tremendous amount of gratitude for all the work that you've done. The effort it takes I know is quite significant. And I look forward to more information, more data, and hopefully we can continue along these kinds of pathways looking at FGFR3 as a target because the initial data, just as you say, is promising. We need the next steps. So thank you once again for all your efforts. But thanks for spending some time with us. We look forward to the next intervention and see where we go next.

Surena Matin: Thanks so much, Sam. I appreciate it.