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Sam Chang: Hi, I'm Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee. And we have both the pleasure and the honor of having Dr. Gopa Iyer from Memorial Sloan Kettering Cancer Center. Dr. Iyer is an associate clinical attending or member there at MSKCC. And I've had the privilege of knowing him for, gosh, maybe 15 or 20 years. We go way back.

Dr. Iyer gave a presentation at the SUO in 2024 at the meeting in Dallas, focusing on actually precision oncology, looking at the role of FGFR3 as a target. And we really appreciate him spending some time and going over and giving us an overview of that presentation, which is very, very well received. But thanks so much for spending some time with us and look forward to hearing your presentation.

Gopa Iyer: Great. Thank you so much, Dr. Chang. It's a pleasure to be here. And thanks also for UroToday for the opportunity to speak today. So yes, as Dr. Chang said, I'm going to talk a little bit about FGFR3 and the role of FGFR3 inhibition in urothelial cancer.

This slide is really just a quick background of FGFR3. We know that fibroblast growth factor receptor 3—it's a receptor tyrosine kinase that's found on the surface of both cancer and non-cancer cells. And it binds to FGF ligands on the surface of these cells. And when that happens, it leads to activation of a lot of downstream signaling pathways from FGFR3, typically the MAP kinase and the PI3 kinase AKT pathways.

What we know about FGFR3 alterations across different stages of bladder cancer is that we see them much more frequently in low-grade disease compared to high-grade disease, and much more frequently in lower-stage disease than in higher-stage disease. This is what we call an OncoPrint. That's basically a summary of the different genetic alterations in low-grade Ta, high-grade Ta, high-grade T1, and then high-grade T2 to T4 disease. This was work that Eugene Pietzak spearheaded and used next-generation sequencing to profile these tumors within each of these stages and grades. And what you see in that red box is FGFR3 alterations—again, enriched really in the low-grade tumors, and then still about 50% of high-grade tumors, about a third of high-grade T1 tumors, and about 15% of muscle-invasive bladder cancer tumors based on the TCGA and other cohorts as well.

There's been a lot of interest in identifying inhibitors of FGFR3. Erdafitinib is really the main one that we have right now. It's a pan-FGFR inhibitor, so it has activity against FGFR1, 2, 3, and 4. And that's a good thing, but at the same time, that also oftentimes results in more toxicity as well. And I'll touch on that shortly.

So erdafitinib is currently the only targeted therapy that's FDA-approved for the treatment of patients with locally advanced or metastatic urothelial cancer that contains FGFR3 alterations. And these patients need to have had at least one prior line of systemic therapy. Typically, in this landscape right now, most patients are getting enfortumab and pembrolizumab, that combination. And then at the time of progression, erdafitinib is definitely an option for those patients who have FGFR3-altered tumors.

This was based on the THOR trial, the phase III trial that compared erdafitinib to chemotherapy and found about a four-month overall survival benefit with erdafitinib compared to chemotherapy, and a hazard ratio of 0.64 in favor of erda. But the big caveat to this drug is the toxicity. About 46% of patients on that study had grade 3 to grade 4 treatment-related adverse events. Most of these AEs are diarrhea, stomatitis, hand-foot syndrome, nail changes like nail dystrophy, and a lot of them do result in having to interrupt the dose of erdafitinib and oftentimes having to dose-reduce the drug as well, which then starts to impact the efficacy of the drug. And then a small proportion of patients can have what's called central serous retinopathy as well, which can lead to fluid beneath the retina and ocular changes as well.

So there are a couple of trials that are ongoing in the non-muscle invasive space because the next step, after the approval in the metastatic space, was to say, well, we know that FGFR3 alterations are quite frequent in non-muscle invasive bladder cancer. What about moving erdafitinib to that space?

So there's the THOR-2 study, which was really spearheaded by James Catto and colleagues. In this study, patients who had Ta or T1 high-grade non-muscle invasive bladder cancer—papillary only, so no CIS—and who were either BCG-unresponsive or experienced were eligible. They were randomized to either erdafitinib or to intravesical chemotherapy. And what they found—I’m going to skip to the very bottom there—is that the median recurrence-free survival with erdafitinib was not reached. So a very active drug, actually, for this patient population. And it was about a little less than 12 months for those patients who got intravesical chemo.

But again, that caveat comes up here because they were only able to randomize 73 patients out of a planned 240 onto that study. There were a lot of issues with accrual. It was in the midst of the pandemic, so that was part of it. But also there were toxicities, and folks were worried about whether patients could tolerate those toxicities. And as you can see, half of patients discontinued erdafitinib due to AEs.

And so there's now a different alternative way to give erdafitinib, which is the TAR-210, which is also called the pretzel device. It’s actually intravesical erdafitinib. It’s inserted through a catheter into the bladder and exchanged about every three months, and it really allows for this local, continuous release of erda over 90 days. There was a phase I trial that looked, again, at a very similar patient population to THOR-2: papillary only, high-grade non-muscle invasive disease, BCG-experienced or unresponsive. Very small group of patients, only 11 that were response-evaluable, but we can already see evidence of significant activity: 9 of those 11 patients were recurrence-free when they looked inside of their bladders, so it's an 82% recurrence-free rate.

The other thing that was very encouraging about this was that only two patients had grade 2 treatment-related adverse events. The vast majority of the adverse events were lower urinary tract–related: hematuria, dysuria, urgency, UTIs—things that were very well-controllable compared to oral erdafitinib. And we weren’t seeing the same issues with nail toxicities, the stomatitis, the diarrhea, when using TAR-210.

So, upcoming trials that I just wanted to quickly spotlight: there’s the MoonRISe-1 trial, which is a phase III study of TAR-210. It’s in patients who have intermediate-risk non-muscle invasive bladder cancer whose tumors also have FGFR3 alterations. For this trial, patients are basically randomized to either TAR-210 or intravesical chemotherapy—either mitomycin C or gemcitabine—and the primary endpoint of this study is disease-free survival.

And then the second trial, which is looking in the muscle invasive space, is the SOGUG-NEOWIN phase II trial. This is randomizing patients with muscle invasive disease who also have an FGFR3 alteration to either erda alone or erda with immunotherapy—with the drug cetrelimab. All of these patients are going to proceed to radical cystectomy, and the primary endpoint here is path CR or downstaging to less than pT2.

Finally, some take-home messages: FGFR3 alterations are detected across all stages of urothelial cancer, but they’re much more prevalent in earlier-stage and lower-grade disease. And erdafitinib currently is the only FDA-approved targeted therapy for patients with FGFR3-altered, locally advanced or metastatic urothelial cancer that’s progressed after at least one line of systemic therapy. It is actively being explored in patients with non-muscle invasive and muscle invasive disease. While oral therapy is very active, it is limited by systemic tox. And intravesical therapy with TAR-210 really represents a very novel treatment approach with limited systemic toxicity and early evidence of significant efficacy in the non-muscle invasive space. Thank you so much.

Sam Chang: Oh, but what a fantastic overview of not only the pathophysiologic overall presence of FGFR3 and its impact, but also then what's ongoing now currently. So let's look at first non-muscle invasive disease and then invasive disease. And in looking at oral erdafitinib now, at least in the fact that it's not too specific for FGFR3, and with its side effects probably too toxic for non-muscle invasive disease. Is that your thought?

Gopa Iyer: That's definitely my thought. I think that there's definitely a higher bar when it comes to side effects in the non-muscle invasive space, which makes sense, especially since we have so many intravesical therapies that don't have these systemic toxicities that are also effective.

Sam Chang: I agree with you totally. Obviously, everybody loves the idea of the non-invasive—take a pill, have it be excreted and work. But the side effect or profile, I think early on, clearly there's efficacy, but clearly I think it's outweighed by—in non-muscle invasive disease. So I think looking at TAR-210 and the utilization of the pretzel, really just as you say, you don't seem to have the diarrhea, the stomatitis, those types of things. And yet the urologists are quite familiar with the lower urinary tract symptoms associated with different intravesical therapy. So it doesn't look too far out of line. So that's great.

Gopa Iyer: Yeah, and then Sam, you know better than me, but I think also just having the 90-day interval about is a pretty typical interval, I think, to do cystoscopic surveillance on these patients. So it aligns nicely with that program.

Sam Chang: I think a really good point that's probably underappreciated by the surgeons is whenever you have that treatment algorithm schedule that does align with clinic visits, et cetera, et cetera, it does really help facilitate and leads to, I think, greater adoption of newer agents when you have something that's more familiar.

In terms of the invasive protocol, looking at basically an IO—the cetrelimab—with or possibly combined with the erdafitinib. This is with the oral erdafitinib, correct?

Gopa Iyer: It is. It is. Yep, and it's a window where patients will get a few weeks of oral erdafitinib alone or oral erda with cetrelimab. And these are all patients, I should mention, that are cisplatin ineligible but have muscle invasive disease. And the plan is still a radical cystectomy. We still don't have any systemic options for those patients, that standard of care, prior to surgery.

Sam Chang: And they have to have FGFR alterations, correct?

Gopa Iyer: Yeah, which may also be an issue. We'll have to see, because it does require central testing. And so from the time of the TUR being done to then getting the testing back, we really need to make that happen in a fairly rapid manner so we can—

Sam Chang: Accelerate it.

Gopa Iyer: Exactly.

Sam Chang: Do you have any idea or thoughts behind the possible synergy between the cetrelimab and erdafitinib? Any thoughts regarding that?

Gopa Iyer: It's a great question. I think that there are definitely data in the metastatic space that might suggest that some of these FGFR3-altered tumors tend to be these colder tumors that may not have as much of an immune infiltration. And part of that could be because there's a suppressive environment there. And so possibly adding IO to that might help to convert that into a more inflamed environment. And then when we add erda to that, we might be able to see some synergy with it.

Sam Chang: See something that's more effective.

Gopa Iyer: Exactly.

Sam Chang: And then obviously, as you go through the presentation that was given at the SUO, I was thinking—and when I hear this again, I'm thinking—well, what about the possibility of the pretzel in invasive disease combined with the cetrelimab to at least get local control, et cetera. In any neoadjuvant treatment, obviously you're looking for more effective treatment of perhaps micrometastatic disease. But that combination seems to be quite effective. So I'll be really interested to see obviously the MoonRISe results as well as the oral erdafitinib to see what happens.

Where next? What do you think next, Gopa, would be exciting in terms of precision oncology, looking at FGFR3 as a target?

Gopa Iyer: As a target, I think one of the things is that there are a few companies that are now developing what they feel are FGFR3-specific inhibitors that are not inhibiting 1, 2, and 4. And so the question will be, is the toxicity profile going to be much better with those drugs such that possibly could we give those even as oral treatments in non-muscle invasive disease? We're going to have to see where the field goes with TAR-210. I mean, if that dominates things, I'm not sure that there's going to be much of a role for the oral inhibitors after that, but—

Sam Chang: Why? Especially like you were saying, for non-muscle invasive disease, we're used to this protocol, we're used—

Gopa Iyer: Exactly.

Sam Chang: —to giving, yeah, exactly. And just as to your point, you have to survey these patients. And so that's—

Gopa Iyer: That's another issue as well.

Sam Chang: We get to the point where we don't have any need for surveillance; we could have urine markers, et cetera. Then something oral becomes even that much more attractive. But in the current paradigm, you're exactly right. So now, exciting times for sure.

Gopa Iyer: Yeah, and Sam, you brought up a great point there because I do think in MoonRISe that they allow for urine detection of FGFR3 as well. So it would be such a great way to do that and probably a much faster way to be able to detect FGFR3 alterations as well, to get patients on study quickly.

In the metastatic space, I think if these FGFR3-specific inhibitors do show significant activity with good tolerability, then they might serve as the basis for combination treatments. Right now, it's hard to do, I would say, with erdafitinib because of the tox.

Sam Chang: So by having that specificity, you would hope, just as you said, you decrease the side effect complication profile.

Gopa Iyer: Exactly.

Sam Chang: And then easier to add other agents as well. So no, it's an exciting time in the different treatment modalities and agents that we have for both non-muscle invasive and invasive bladder cancer.

And we really look forward to your continued contributions and those of others at Memorial Sloan Kettering in terms of actually making a real impact. So Gopa, it's always good talking to you and great catching up. And we're so happy to see how well-received your presentation was at the SUO.

Gopa Iyer: Oh, thank you so much again for the opportunity. It's always a pleasure to chat with you, Sam, and with the UroToday folks. Thanks again.