Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia, delighted to be joined back on UroToday with Dr. Tom Jayram, who is a urologist at Urology Associates in Nashville. Today, we're going to be discussing the SURF302 study, a really exciting potential oral treatment for intermediate risk non-muscle invasive bladder cancer. Tom, always appreciate your time and thanks for joining us on UroToday.

Gautam Jayram: Thanks, Zach.

Zachary Klaassen: Just before we get into this exciting trial that you're a part of, just level set for our listeners what intermediate risk non-muscle invasive bladder cancer, it's kind of a bit of a gray zone, so to speak, and why it's been of huge clinical interest over the last several years.

Gautam Jayram: Yeah, it is really very interesting how much excitement new therapies and trials have been devoted to this space over the last five years. So, intermediate risk bladder cancer is really a subset of patients who have really, what I would say, nuisance, low-grade disease, this is low-grade cancers that recur within a year, multifocal, and then a really small subset of patients who have high-grade disease. And what's interesting is, is depending on who you ask, maybe those two shouldn't be grouped in under intermediate risk, in Europe, the guidelines put all high-grade patients into a high-risk bucket, but there is some good data that says that potentially small high-grade patients can behave similar to some of these bulkier low-grade patients in terms of their response or their need for intravesical therapy afterwards. So, it really defines a group of patients who have a very low risk of progression, but generally speaking, have a high risk of recurrence. So, I call it nuisance bladder cancers as opposed to dangerous bladder cancers, and I think what also has set the stage for all of this inquiry into this space is there really isn't that much out there for it. The guidelines suggest single agent intravesical chemotherapy might be an option, I can tell you in community practice, it's really, really, really not utilized, and I think probably similar in academic practice, everyone's probably utilizing some perioperative single dose chemotherapy, but doing induction, gemcitabine or induction mitomycin, it just isn't that common. And so, the question becomes is what do you do for these patients? With the BCG shortage, we're trying not to utilize BCG. And so, it's kind of an open form of what can we give these patients to reduce their risk of recurrence. And so, I think that's why there's been so much interest in this space.

Zachary Klaassen: Yeah, great answer. I think you're absolutely right, we don't want to use BCG in these patients, we have high risk patients who want to use it on. What are we going to use for them? Let's shift to FGFR3 inhibition, why is this of interest in intermediate risk disease, and how could a good therapy potentially decrease burden of repeat resections? Like you said, they're not going to necessarily progress, but they're going to recur, recur, recur.

Gautam Jayram: Yeah. The FGFR story in bladder is pretty interesting. Erdafitinib was approved, I think, three or four years ago in the metastatic space for patients who had failed chemotherapy and patients who had failed checkpoint inhibitors, and what we saw then was about 20, 30% of patients maybe had an FGFR alteration. The biology of FGFR is basically it impacts tumor genesis. It's an oncogene, basically it promotes tumor growth, and so the FGFR inhibitors have been shown to decrease that. What's really fascinating is in this intermediate risk subset, specifically in low grade patients, you really see a high proportion of patients with FGFR alterations. There's kind of two ways to test, you can test urine and you can test tissue, tissue always obviously has a higher yield, but the studies we're seeing right now, urine testing is shown about 40%, 30 to 40% of patients, but the gold standard is tissue, and we're seeing 70 to almost 80% in some studies of expression of an FGFR alteration in low grade. So, it's everywhere in these patients, it's a very high incidence, and it's ripe to be a target in that situation. So, I think that's the rationale is that it's very commonly altered in these patients, and that it may be an oncogenic driver of tumor recurrence.

Zachary Klaassen: Yeah, especially with four out of five patients potentially having a target in that population, that kind of leads me to TYRA-300. Tell us about that and set the landscape for the SURF302 study, which you're a part of.

Gautam Jayram: Yeah. So, dabogratinib is a drug in this space, it's what we would consider kind of a novel super selective or selective FGFR inhibitor. So, erdafitinib, which we mentioned, it was first in class in terms of FGFR inhibition, but a pretty toxic drug. If you talk to medical oncologists, they don't love using that drug because of what they call off-target toxicities. You get a lot of TKI-like toxicities, mucosal issues, nail bed issues, phosphate and odd laboratory issues, ophthalmologic issues... And erdafitinib orally has been tried in NMIBC, there was a study called the THOR trial, T-H-O-R trial, where we were giving oral erdafitinib for these patients. And I will say, from an efficacy standpoint, it is really fascinating because it does work, it ablates tumors, you're just getting a ton of these off-target toxicities, and it's a really hard sell, especially in intermediate risk disease when you really have a very low risk of cancer progression. So, the cool thing now is dabogratinib is a selective FGFR3 inhibitor, it does not capture those off-target toxicities, and diarrhea and maybe a very mild phosphate disturbance are what we are seeing, but it is much more... The hope is that it's much more applicable to this population and the tolerability is going to be much higher.

Zachary Klaassen: No, that's great. I think when you look at these options, we've just come off of recently ESMO 2025 where we've seen a push towards personalization HER2, then first-line metastatic urothelial carcinoma with disitamab vedotin/toripalimab. We're moving now potentially to molecular profiling being really important for these patients, identifying these FGFR3 targets. So, how does this maybe have a broader landscape for continuing to push sequencing of these tumors?

Gautam Jayram: Yeah, this is going to be, I think, where we're going with all of this is personalizing this approach, doing a cysto and a TURBT, profiling that tissue, and then understanding that maybe not all patients should receive the same therapy upfront. And we're starting to see this in high-risk disease too, with some of the artificial intelligence testing that we're doing, different patients may benefit differently from frontline BCG versus Gem/Doce versus a novel agent. So, I really think this is where we're heading. Urologists who maybe have some experience in advanced prostate cancer have some experience in tissue testing, somatic mutations, and the implications. So, I don't think this is a big reach, obviously, it is one more step, but I think in sophisticated centers and in places that are doing trials and places that are doing all of these novel therapies, I don't think it's a lot to ask for. And certainly, I will tell you, patients respond really well to this. When you tell them, listen, this isn't a blanket therapy, this is something that we're only going to treat you with if we find out that you have this alteration and the data is really good, if you have the alteration, I think everyone is really excited about it.

Zachary Klaassen: No, that's great. Tell us a little bit about just the update of the SURF302 trial, and maybe just as you led into a little bit how patients are, an oral therapy versus intravesical versus IV, urologists I'm sure are going to love this, the patients I'm sure are amenable to it. So, maybe just in your workflow and what's the update on the trial to date?

Gautam Jayram: Yeah. So SURF302 is an interesting trial, multicenter open label phase two, so we're using dabogratinib in that group of patients that is intermediate risk, but low grade only. So, we're not testing in high grade yet, and those patients have to have an FGFR alteration. So, again, and you can really test however you want, either tissue or urine, which is nice, because again, in some of the other trials in this space, we're limited to a urine assay and we're just not finding as many patients as we should. So, we talked about the role for oral therapies in this disease space, which I think is really interesting, and I think is the big question here, is how do urologists and patients... But I'm kind of more interested in urologists' interest and uptake of an oral therapy in this space. And anecdotally, my experience has been that I'm generally interested in it, my partners are interested in it, and patients, there's definitely a subset of patients who are interested in it. So, obviously the whole goal with all therapies in this space is to maybe delay TURBTs, increase intervals to TURBTs, less interventions, but then also not having to be tied to a catheter instillation or a device instillation, and once a week for six weeks, once every three weeks, I think we underestimate the burden that that has on patients. So, for example, I just talked to a patient who's interested in the trial who when we talked about some of the options in this space, some of the on label options versus some of the trials, they said, "Well, I travel a lot and a tablet would be way easier for me to do." So, I think we have to keep that in mind, there is a burden of intravesical therapy on these patients, they don't enjoy being catheterized. And the whole thing here is going to be the tolerability. If the tolerability makes sense, then I think it is really compelling, and I think what's cool is, is this is potentially paradigm shifting and we'll probably start inviting some other study in this space because we're so used to, well, it's in the bladder, we don't want to do anything systemic, we just want to do local, which makes sense for a lot of reasons, but if you can get that tolerability profile better, there are some real benefits for both patients and urology practices by giving something oral.

Zachary Klaassen: Yeah, no, absolutely, Tom. Always great chatting with you. Anything we didn't hit on, anything you wanted to leave our listeners with?

Gautam Jayram: No, I think this is an exciting space, there's a lot of trials in this space, and really I think the key is what we've already talked about, is the changing nature of the delivery system. We've talked about this is we've got an oral tablet now, we've got gels, we've got devices that are eluting targeted therapies. So, the delivery system is changing, and I think there's going to be a lot of interest in how things are, but really ultimately it just serves to increase a number of options for our patients, patients don't have to necessarily commit to catheter-based instillations or just one line of therapy, one modality, which I think is really interesting and really serves a lot of promise for the future.

Zachary Klaassen: No, for sure, we'll definitely keep an eye on SURF302, as always, thank you for your time on UroToday, Tom.

Gautam Jayram: Thanks so much.