Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence, I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and it's a pleasure to welcome a repeat guest and someone that really needs no introduction, Professor Siamak Daneshmand from USC.

Sia, thanks for taking the time today to follow up with us on your GU ASCO presentation on a very important trial, which is essentially the safety and efficacy of Erda in patients with intermediate-risk non-muscle invasive bladder cancer. Really some exciting stuff in this field, especially with this data. So if you could share with us your thoughts, and then we'll go on a little Q&A at the end?

Siamak Daneshmand: Absolutely. Thanks so much, Ashish, for having me on again. It's a real pleasure. Yeah, this was exciting. This was the preliminary results of this Phase 2 study looking at Erda in intermediate-risk and low-grade patients, which is different than what we've been looking at in the main study, the THOR-2, Cohort 1 and 2 in the BCG unresponsive disease.

So this was a separate cohort. I'll just go through some slides to show you the preliminary data that we just presented at GU ASCO. So, yeah, our treatment paradigm right now for papillary anomalous invasive bladder cancer includes some adjuvant therapies, typically gemcitabine after the TURBT.

There's some approaches to leaving some marker lesion behind it, seeing if there's efficacy to topical treatment or any other treatment, so this was a study of erdafitinib, which is well known to many of us, but for those who don't know, it's an oral selective pan-FGFR tyrosine kinase inhibitor. So it's approved for locally advances in metastatic disease in patients who harbor the FGFR3 mutations or alterations, who've progressed after one line of platinum-containing chemotherapy. So it's currently in use for metastatic patients, and then this THOR-2 study that I mentioned is a multi-cohort Phase II study of erdafitinib in patients with non-muscle invasive bladder cancer.

So, the real objective of this study was to look at the efficacy and safety results of Cohort 3. So again, this was an additional cohort of the THOR-2 study, and looking at the exploratory outcomes of intermediate-risk non-muscle invasive bladder cancer patients with FGFR-altered disease. So this was mostly low grade patients, these were non-muscle invasive bladder cancer patients with recurrence or intermediate risk like we mentioned, grade 1 to 2 or low grade Ta. We didn't have any T1s, but no previous CIS.

The risk of progression should be very low in the next two years, and risk of progression, I'm sorry, risk of recurrence should be more than 50%, as we know they are in this patient population. And we have very limited treatment options for these patients. We've used intravesical chemotherapy generally, but there's not much else for these patients. So, in this study you had to resect all the tumors except leave one untouched tumor, about five to 10 millimeters. That was your marker lesion to see, to look at the efficacy of this treatment. And then patients received continuous oral erdafitinib, six milligrams once daily, without any up titration in a 28-day cycle.

The dose used for metastatic disease is nine milligrams, so this is less toxic than nine milligrams. And then patients who had a partial response or complete response were allowed to continue erdafitinib for a maximum of two years, or progressive disease, or if they had intolerable toxicity. So this is the design. Again, I just want to highlight Cohort 1 and 2 a little bit. Those are for high-risk non-muscle invasive bladder cancer for BCG unresponsive disease.

Cohort 1 is papillary only, without CIS, and Cohort 2 is CIS with or without papillary disease. And they get erdafitinib in a much, much bigger study, 240 patients randomized to erdafitinib versus investigative choice of gemcitabine or mitomycin or hyperthermic mitomycin for those who have it in the international community. And then looking at recurrence-free survival in those patients, the patients with CIS, there's only 20 in that cohort with CR, we're looking at CR rates at six months.

So down to the green box here, this is Cohort 3, again, was this exploratory cohort looking at intermediate-risk erdafitinib, 20 patients with the exploratory endpoint being CR rates, and key secondary endpoint being safety. So, little bit different, using oral medication to treat low grade disease. And here are the baseline characteristics of these patients. So, we had 10 of 11 patients enrolled by the data cut-off point in September of 2022. The median follow-up was about six months. They received the erdafitinib for median of three months, median age 66.

And you can see the breakdown of the sex, race, and ethnicity there. This was an international study, so we did have some European participants as well as South America. So here are the tumor characteristics, like I said, most of these... All of these were TA tumors, we didn't have any T1.

There were 10 patients evaluable here, and most of them were ECOG 0. And you can see the different alterations there. So, one thing to note is that in low grade tumors, the FGFR3 alterations are seen in approximately 80% of patients as opposed to high grade, where it's seen in about 20 to 30%. So of the three patients I had that we sent off for analysis, all three ended up having the mutation.

So it is much more common, and here's the key slide here, that with eight evaluable patients, six of whom had complete response. So 75% is really quite something, to watch these tumors go away. You know exactly, you left this marker lesion, we took pictures, and on the next cystoscopy, these completely disappear. So, you can see the graph there, the swimmer plot of the CR rates, and these are for the most part early responses.

You can see the response as early as six weeks with oral treatment, and a median duration of response has not yet been reached because of the patients' ongoing responses with a cystoscopy. So really, really exciting stuff. I mean, when you see tumors completely disappearing so quickly, it's really encouraging. And we can really expand on this concept.

In terms of safety, this is a well-known safety profile. The treatment-related adverse events, there were good number in most of the patients, but grade 3s were uncommon that were treatment-related. There's only one patient that had a grade 3 adverse event that we thought was related to the drug, but most of the adverse events were really low grade.

No serious adverse events and nothing leading to study discontinuation. So again, the most common ones were grade 1 and 2. Almost everybody gets hyperphosphatemia, that's almost a marker of whether this drug is working or not. And then patients, a few got diarrhea, dry mouth, dysgeusia, and others are like hair changes. Fortunately, we didn't see as much nail changes as we do in the higher dose erdafitinib use for metastatic disease.

So really, this demonstrates the anti-tumor activity in intermediate-risk disease, something we've not seen before. Again, this is an oral drug, the CR rates so far, and its preliminary analysis was 75%, and many of the patients are ongoing on the treatment. So, we'll see where this goes. There's no serious treatment-related adverse events. So, we're really excited about these prelim results, and I think again, it really opens up the avenue for further studies.

Ashish Kamat: Thanks, Sia. I mean, again, a very nice listening presentation. Couple of questions and you and I have talked about this disease space for many, many years. I think one of the strengths of this cohort is that it's the true intermediate-risk patients as we clinicians think about them, the low grade patients, not muddying up the waters with the high grade, small TA, with all that, that goes in. That being said, what platform do you use in this study to assess the mutations? And how long is the turnover for the patient in real time?

Siamak Daneshmand: Yeah, great question. This was Foundation, and the turnaround was around two weeks. At least that was in the US. I'm not sure in Europe, but I think it was similar, but it really doesn't take that long. One thing to add, the nice thing is actually, if you had tissue from before, because these are intermediate-risk, they've had low grade tumors in the past, if you had a TURBT specimen from before, you could send that previous block because most of these patients harbor the mutations throughout their recurrences. So, it didn't have to be the index one that you just did.

Ashish Kamat: Right, right. I was also going to say that I'm sure you were part of the other studies where we're using urine in order to get the same mutation analyses and don't have to rely on the block. So, hopefully that whole paradigm will become a little bit faster for patients. But two weeks is certainly, especially in this patient cohort, intermediate-risk, it's not an issue, per se.

Now what is your sense, and I know the numbers are small, but they're still very encouraging, but based on the fact that it's an oral agent which has toxicity and it's a low grade tumor in the bladder, but you're getting 75% CR rates, what's your sense having obviously treated tons of these patients in the past, some with active surveillance, some with gemcitabine, some with this agent, where do you think this will land if the data holds true?

Siamak Daneshmand: Yeah, it's a great question, and I think I've thought about it myself as I'm treating these patients thinking, "When do we stop?" Let's say this gets approved for this setting, and what are we going to do? So I think in my mind, when we see these tumors, we think, "Okay, you need a TURBT. We're looking at the tumor, the patient's looking at the tumor."

And how I'm envisioning it is we treat the patients for a period of time, the tumors go away, and we're doing this intermittent therapy, and if the toxicities are tolerable, then we can treat them intermittently, have these tumors go away. Or the patient who has very large volume disease in the bladder and we really can't be scraping the entire bladder, and we're pretty sure this is mostly low grade, they harbor the mutation, use the drug as an ongoing therapy instead of taking them for a TURBT that's not feasible, and other patients who it's difficult to take them to the OR.

Now obviously like you said, we have other treatment options, we can treat them in the clinic if they're small tumors, that's not how I'm envisioning. But if I see a one-centimeter or less tumor, and I'm probably going to just ablate that tumor in the office. But we're talking about the multiple papillary diverticular type disease or very old patients with a significant volume of disease.

And the other area to think about it is the upper tract. This is something we haven't really explored. Right now we have JELMYTO, that's the FDA approved drug for that. But again, there's some limitations for JELMYTO, the volume of disease is an issue. So if we have a larger volume in a solitary kidney or someone who can't tolerate, and therefore ureterectomy, if they harbor the FGFR3 mutation, this would be the perfect space for using medication to decrease the volume and actually develop, go to a CR in the upper tract. That would be a home run.

Ashish Kamat: Yeah, I can almost envision this being first line therapy. You detect a tumor in the upper tract, you do your cytology, whatever you need to, to make sure it's low grade. And you might not even need tissue because of the immense correlation between grade and FGFR mutations, I could envision somehow this being first line therapy for the upper tracts even before you go in and try to ablate those with laser or whatever.

Yeah, I think you hit that right on the head. I think that's where this will really land. A couple other practical questions for you, Sia, and not related specifically to the abstract, but we treat a lot of patients or observe a lot of patients nowadays that have low grade history and may have one or two tumors in the bladder. Again, based on some of the Italian studies, et cetera, on active surveillance.

Do you think that having an oral agent or any agent that addresses that active surveillance population will help you monitor more patients on active surveillance because you might be able to treat them orally, or do you think that active surveillance is going to cannibalize these sorts of cohorts or studies down the road?

Siamak Daneshmand: Yeah, great question, and Mark Solloway's been talking to us for years about active surveillance for low grade tumors. I agree. I mean, there's certainly a certain population who really doesn't progress and their tumors are very indolent, they grow very slowly. But when we're doing cystos in the clinic and the patients are looking at recurrent tumors and they know they've been through multiple TURBTs, it's a little bit different conversation. We can tell them all day, "This is a not very aggressive tumor."

The progression rates are very, very low. But nevertheless, the concept of having a tumor leftover in your bladder I think psychologically doesn't go so well as it does perhaps in renal cell carcinoma, small renal masses, or low grade prostate cancer that they can't really visualize or see in their mind. But I think there's going to be a combination of therapies.

I think the paradigm is going to shift for low grade tumors where this knee-jerk TURBT has to happen for low grade tumors. I think there's going to be a population where we observe. There's going to be some small tumors, which we can ablate with our better endoscopic tools that we have, and you can see these tumors with blue lights, we can ablate them in the office, and not take them to the OR. And then for another subset of patients, we're going to have oral erdafitinib, and I think it's going to be very, very convenient for us to write a prescription for an oral drug.

The patients are going to I think tolerate it fairly well, and for those who have toxicity, we can take them off. We haven't even explored the even lower doses of drug to see whether that is efficacious with less toxicity.

Ashish Kamat: Right, and also different mechanisms of administration of Erda. You could have the potential intravesical pretzel delivery system, the Erda risk, and that's a whole different topic. But I like what you suggested, and that's what we've been envisioning a little bit too. You could essentially have a patient that has a tumor that you and I as clinicians know would be totally safe for active surveillance, but then tell the patient, "Hey, active surveillance is one option, but if you're worried and if you want to try this oral agent, here, you have that." Right?

So essentially, let the patient be a part of that informed decision, which I think is the way we should do all of this anyways. Sia, it's always great to chat with you. In closing, any high level thoughts you want to leave with the audience, either related to this particular abstract or where this is heading?

Siamak Daneshmand: Yeah, thank you again, stay tuned. I mean, there's more coming, and I think you mentioned it at the Erda risk, that is a new trial that is going to be ongoing and starting in some countries and soon in the US, looking at erdafitinib within a sustained delivery system with a pretzel in the bladder. So hopefully, that will further decrease the systemic toxicity, and that will be a really ideal drug to use in the bladder if we see the same efficacy. So, stay tuned. I think we've got some exciting things going on.

Ashish Kamat: Thanks again.

Siamak Daneshmand: Thank you.