Intravesical Erdafitinib (TAR-210) Demonstrates High Response Rates in NMIBC With Reduced Toxicity - Roger Li

March 4, 2024

Sam Chang engages with Roger Li to delve into the TAR-210 study, focusing on bladder-based intravesical therapy targeting FGFR3 in non-muscle invasive bladder cancer (NMIBC) patients. Dr. Li shares insights from the multi-site international study, highlighting the efficacy of Erdafitinib, particularly in patients with FGFR alterations. Despite the challenges with oral Erdafitinib's toxicity, the intravesical TAR-210 presents a promising alternative, demonstrating remarkable complete response rates in early findings. The study's innovative approach includes using urine studies for detecting FGFR alterations, offering a non-invasive method to identify suitable candidates for this targeted therapy. Dr. Li's discussion also touches on future directions for TAR-210, including a phase three randomized control trial, emphasizing the potential of urine-based diagnostics to predict treatment outcomes and monitor resistance.


Roger Li, MD, Genitourinary Oncologist, Moffitt Cancer Center, Tampa, FL

Sam S. Chang, MD, MBA, Urologist, Vanderbilt University Medical Center, Nashville, TN

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Sam Chang: Hi, my name is Sam Chang. I'm a urologist at Vanderbilt University, and today we're quite fortunate to have Roger Li from Moffitt Cancer Center here. And we're going to focus a little bit on the TAR-210 study, which is looking at bladder-based intravesical therapy utilizing, actually binding to FGFR3, and want to know a little bit about TAR-210, but most importantly also want to know kind of in those patients, perhaps it's going to be more or less effective based upon urine studies. So, Roger, first of all, thank you so much for being here and look forward to hearing what you have to say.

Roger Li: Thanks so much, Sam, and very delighted to be here with you today. So, we're participating in the TAR-210 study, which actually is a multi-site international study that recently reported out at ESMO just a few months ago. And really, the impetus for studying Erdafitinib in the non-muscle invasive bladder cancer setting stems from the fact that up to 70% of especially low-grade NMIBC patients harbor some sort of FGFR alterations. And as you know, the THOR study had recently just read out in the papillary BCG-exposed population cohort, even though the study was stopped short because of accrual issues, they did find that there was a significant improvement in RFS as compared to intravesical chemotherapy of dealer's choice. So, the primary endpoint was the recurrence-free survival. But just to illustrate, the 12-month recurrence-free survival for patients who are on oral Erda was around 77% as compared to only 40% on intravesical therapy.

Sam Chang: Intravesical therapy.

Roger Li: Yep.

Sam Chang: But the downside of the oral Erdafitinib really kind of detracted from its success in terms of its efficacy. And so, hence, the next step being...

Roger Li: Exactly, so as you pointed out, the toxicity of oral Erda, which on that trial was slated out to be a continuous two-year administration, interestingly enough, only one patient had the wherewithal to continuously take that for the entire duration of the study. So, the toxicity was real, and especially for this patient population, you could imagine that they don't want to deal with all of these toxicities. And hence, the rationale for the intravesical TAR-210, which as you alluded to earlier, is this pretzel-shaped drug-eluting stent that continuously eludes out Erdafitinib within the bladder. The same platform has been studied in the TAR-200 SunRISe studies, as you know, with intravesical chemotherapy. But in this setting, it's really a more targeted approach with Erdafitinib targeting FGFR3-altered bladder tumors. So, the study really is broken down into four different cohorts. Of interest to us today are cohort one and three.

Sam Chang: Okay.

Roger Li: So, in cohort one, these patients are high-risk NMIBC patients that have been exposed to BCG. On that study, they are required to have all of their tumors resected before placing the TAR-210 agent. So, it's really an adjuvant study.

Sam Chang: Right.

Roger Li: But more interestingly, the cohort three patients are intermediate-risk NMIBC patients, some of whom have not even had any tumor resected at the time of the study start.

Sam Chang: Okay.

Roger Li: And so really, as almost a marker lesion, except some of these patients have eight to 10 tumors in the bladder.

Sam Chang: And these are BCG naive; they've not received BCG. So very different cohorts of patients.

Roger Li: Right. Two very different cohorts. But in cohort number three, you place the TAR and then you look at three months to see whether just by placing the TAR-210, whether the tumors melt away. And so the top line was really read out at ESMO just a few months ago, where they reported out 87% complete response even in that cohort three with preexisting tumors left in situ. So pretty remarkable compared to even the data that we know about intravesical chemotherapy and such in the past, whereas for the high-risk NMIBC patients equally as good. So 82% complete response out to the three-month mark. So really, I think if you have an FGFR alteration... So really, from even the short-term data, we know that the TAR-210 product is really a great drug that has at least great short-term efficacy along with tolerability and really limited the amount of toxicity that we're seeing.

Sam Chang: So not only effective in a higher-risk cohort of patients that would fit the definition of BCG unresponsive, but for those intermediate-risk tumors, I mean true ablation of tumors with placement of this. And then along those lines, tell me a little bit about what the urine sulfur DNA showed. I mean, clearly a holy grail is you give us a urine sample, tumor, yes, no, etc. So tell me about the results they're looking at, kind of the urine studies associated with the TAR-210 patients.

Roger Li: Yeah. So just to back up a step or two and give some background on the THOR2 study, which enrolled patients with oral Erda, they had about a 40% fail rate in terms of, because they used tissue samples to understand whether there was any FGFR alterations. And so really, the impetus for using the urine, especially for those cohort three patients whom we don't have any tissue samples.

Sam Chang: Yeah. Exactly. Still had tumor in place.

Roger Li: So for them, they also could use their tissue samples that were collected from the previous TURBT as a surrogate.

Sam Chang: Okay.

Roger Li: But the alternative was to submit a urine sample to understand whether they have an FGFR alteration in the urine at the start of this study.

Sam Chang: All right.

Roger Li: And so what we found was between the two methods of finding FGFR, -

Sam Chang: Either tissue-based or urine-based only.

Roger Li: That's right.

Sam Chang: All right.

Roger Li: They performed relatively equally well. So about 60% viability from either the urine or the tissue sample.

Sam Chang: Okay.

Roger Li: Now, the caveat for that is they're complementary. So in some of the patients who did have enough tissue samples, they didn't have a sufficient urine sample to understand the FGFR status and vice versa, some patients who had adequate urine samples but did not have adequate tissue samples. So between the two tests together, out of 180 patients that were screened, more or less, there were only 18 patients that failed screening because of insufficient sampling.

Sam Chang: Understood. All right.

Roger Li: So it's kind of like an alternative test that helps to capture more patients.

Sam Chang: That may have FGFR alterations.

Roger Li: That's exactly right. And it comes especially handy for these patients in cohort three, again, who are not undergoing a TURBT, who may have limited samples from previous TURs, who then can have the opportunity to enroll onto this study.

Sam Chang: And actually not necessarily have the need to do a TURBT because you don't have to have the tissue, but then go ahead and actually proceed with therapy that may ablate their tumors totally without. And then have you looked at post-treatment urine tests yet,

Roger Li: Yeah.

Sam Chang: Within this trial? And if it's too early and we can't report on this, tell us. But to me, it'd be fascinating as well in terms of pre-treatment response versus post-treatment urine-based studies.

Roger Li: Absolutely.

Sam Chang: Yeah.

Roger Li: Absolutely. Very insightful question and very similar question as we're posing as well. So on study, they are collecting urine samples, so there's going to be an adequate amount of urine samples to use. And so Lexi Wynn, who is a current resident from the Mayo Clinic, who's coming into Moffitt to start her fellowship next year, actually put in an AUA Foundation, Care Foundation proposal to study exactly this question. So we're going to be collecting urine samples from pre-treatment and also on treatment for these cohort three patients because they come back at six weeks into their treatment for a cystoscopic evaluation, and then at three months and then every three months thereafter. So we're going to be using these longitudinally collected urine samples, not only to use the panel test that was included in the study per se,

Sam Chang: In the actual study. Sure, okay.

Roger Li: But again, we're going to be doing it in a tumor-informed bespoke manner, not only to understand the FGFR mutations per se, but just across the landscape. What are the mutations that these patients are starting out with,

Sam Chang: In the urine.

Roger Li: In the urine?

Sam Chang: Yeah.

Roger Li: And you can also, so some of these patients may have had TURBT,

Sam Chang: Tissue as well, so you'll have that as well. Sure.

Roger Li: And then you can track these mutations throughout their treatment course. And the advantage of doing it this way is this is targeted therapy. And from our experience with targeted therapies in the past, especially when delivered in such a sustained manner, patients, some patients at least, will develop treatment resistance down the line. So when we're using these urine samples, we can also maybe predate the clinical recurrence for these patients to understand what are the mechanisms that are underpinning these tumors that are recurring.

Sam Chang: So a combination of not only having diagnostic benefit but also therapeutic predictive benefit,

Roger Li: That's right.

Sam Chang: Of what's actually going to happen in these patients. And all just based on a urine simple voided sample, not a wash, not... Just from a urine sample being able to find those results. It's amazing.

Roger Li: Yeah.

Sam Chang: And so as the current trial comes to a conclusion and you look at not only its efficacy in terms of tumor destruction and cancer-free rates, what's the next step you think then for TAR-210? You've got a four-arm trial looking at different cohorts. Is there a move towards looking at more invasive disease, although not as likely perhaps to have this mutation in higher grade or higher risk disease? What's the next step you think with TAR-210?

Roger Li: Great insights once again. So as part of the initial phase one study, they did include an arm with muscle-invasive bladder cancer patients who have the option of being treated with TAR-210 for about two weeks before going on to,

Sam Chang: To cystectomy.

Roger Li: Radical cystectomy.

Sam Chang: All right.

Roger Li: So that is being addressed. But the next step for this product is really a phase three randomized control trial in the intermediate-risk NMIBC setting, because as we know, the incidence of FGFR alterations is the highest in that,

Sam Chang: In that cohort or in that population of patients.

Roger Li: Correct. Up to 70%. So great odds at picking up FGFR alterations really to compare the efficacy of TAR-210 in the adjuvant setting. So now that we've established this efficacy as a tumor ablating agent,

Sam Chang: Sure.

Roger Li: How does it work in the adjuvant setting when these tumors are resected?

Sam Chang: Right.

Roger Li: Presumably even better.

Sam Chang: Better. Right.

Roger Li: Compared against dealer's choice, intravesical chemotherapy.

Sam Chang: Very exciting times, Roger. I really appreciate you spending some time with us,

Roger Li: Absolutely.

Sam Chang: And giving us insights regarding TAR-210, but also hopefully the urine test that you're looking at will be able to help provide even more answers in the future, so.

Roger Li: Yeah, absolutely. Thanks again for having me.

Sam Chang: Thanks again, Roger. Look forward to the next trials that you'll be involved in and helping us actually learn a lot more about bladder cancer.

Roger Li: Appreciate that. Thank you.