A roundtable discussion, moderated by Thomas Powles, MBBS, MRCP, MD, covered the latest updates in bladder cancer treatment and research, including recent data from ESMO 2023. Dr. Powles was joined by Shilpa Gupta, MD; Sia Daneshmand, MD; and Petros Grivas, MD.
In the next segment of the roundtable series, the panel discusses other exciting treatment advances in bladder cancer, including the “novel delivery mechanism” in the TAR program.
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Dr. Powles: I want to move to the next steps, and 1 of which is around the ADC [antibody-drug conjugate] doublet story. We saw at ESMO Brad [McGregor, MD] presented a really nice investigate-initiated phase 1 trial of enfortumab vedotin (EV) plus sacituzumab govitecan. Sacituzumab govitecan is a Trop-2 ADC. It has SN-38, a topoisomerase 1 inhibitor as the payload. Those 2 drugs seem to be active together with response rates of 70% and manageable toxicity. Shilpa, what was your take on that phase 1 trial, and what does it mean for us moving forward?
Dr. Gupta: I think it was a good study to show that it’s doable with non-overlapping toxicities and short responses in a majority of patients. But the toxicity can be challenging even though they’re not overlapping, and I think one needs to come up, it’s good to see that these trials are doable and there’s efficacy; I think just the dose optimization and how many cycles we need and then followed by maintenance therapies.
Dr. Powles: Do you think we’re going to be doing more doublet/triplet trials? Is this study that the start of a new group of trials, or do you think it’s going to be really challenging?
Dr. Gupta: I think if they move to the frontline, the bar that EV-302 has now raised, it’ll be really difficult to beat that unless we have a really promising ADC, which we can add to EV/pembrolizumab to beat that. I think that is going to be the next step. In your discussion like you had outlined, the 2 antibody drug conjugates and immunotherapy and then go from there. I think we really need to be careful. We don’t want to be like the kidney cancer world where we are throwing the kitchen sink at the patient at the risk of toxicity.
Dr. Powles: We’re going to do better than kidney cancer. Petros, there was a study called THOR. THOR actually has 2 cohorts and it tests erdafitinib, which is an FGFR inhibitor, in patients with FGFR alterations. In cohort 1, which we’ve seen before to be fair, compared erdafitinib with chemotherapy in heavily pretreated patients and showed that erdafitinib was significantly better, both from progression-free, overall survival, and response rates, with about a 36% reduction in the risk of death, which was really attractive. But then at ESMO we saw a more confusing trial or more confusing results in my opinion, where the erdafitinib in these FGFR patients was compared with pembrolizumab and we showed there a hazard ratio for survival of 1.18. What happened in that trial and why have we got these divergent results?
Dr. Grivas: Tom, great point again. One message for the audience is that we need to test with next-generation sequencing cancer tissue at the time of diagnosis of metastatic disease, in order to inform our subsequent therapy steps and to see whether erdafitinib may be an option in patients who have FGFR2 or FGFR3 activating mutation or effusion. We did an adjuvant trial, that is separate story, that did not fully accrue, but in the metastatic disease we need to test cancer tissue for FGFR2 and FGFR3 activated mutation of effusion. It’s important to look at the fine print on these genomic panels to make sure these genes and assays are included in the tests because sometimes may be missed. With that background in mind, we have the THOR trial, 2 different cohorts as Tom you alluded to. Cohort 1, that was a very important question, erdafitinib in this selected patient population versus taxane in the United States or vinflunine in Europe, in patients with prior immunotherapy and most of them had prior platinum-based chemotherapy.
This was a population of patients: erdafitinib versus taxane or vinflunine and there was a clear overall survival benefit hazard ratio 0.64 favoring erdafitinib in this selected patient population, which about 20% of patients in our practice have this mutation or effusion FGFR2, FGFR3. I think Dr. Loriot saw the data with a subset of patients and more or less with different degrees of benefit, patients across different subsets that had benefit with erdafitinib versus chemotherapy, taxane/vinflunine.
Now the second question, the second cohort of this trial was erdafitinib versus pembrolizumab in the second line in platinum-refractory population. Patients had platinum chemotherapy, had progression, did not get avelumab maintenance in that sense, and they had erdafitinib or pembrolizumab again in the selected population with FGFR2 or FGFR3 mutation or effusion. That trial showed an interesting result. There was no significant difference in overall survival or PFS [progression-frees survival] with erdafitinib versus pembrolizumab in the selected population in the platinum refractory setting.
Now, you may argue that the PFS slightly numerically favored erdafitinib, but there was no significant difference. A response rate almost double in favor of erdafitinib: 40% with erdafitinib, 22% with pembrolizumab. My practical take on it is number 1, pembrolizumab is likely to move frontline based on the EV-302 trial. This data may be less applicable in the future, at least in the United States and countries with access to pembrolizumab/EV. Having said that, I think it helps us select the sequence of therapy if someone is in the dilemma between erdafitinib and pembrolizumab after a potential prior platinum-based chemotherapy or prior EV and you’re between erdafitinib and pembrolizumab, if you need a response right away, visceral metastasis, liver metastases, explosive symptomatic disease, high disease burden, I would go for erdafitinib. The advantage with pembrolizumab is if you get a response, 22%, this response can be durable. The tail of the curve came and pretty much you ended up with high responses with erdafitinib, tail of the curve with pembrolizumab similar to what we saw with TKI [tyrosine kinase inhibitor] and IO [immunotherapy] and kidney cancer, Tom. No OS benefit at the end of the day between the 2 agents. The patient selection where you use erdafitinib versus pembrolizumab in these patients.
Dr. Powles: Do you think the biomarker is fabulous?
Dr. Gupta: I think it’s a good step in the right direction and like Petros said, we should test everybody. I think for the FGFR, yeah, it is fabulous because we have a drug for it. But for treatment selection in general for immunotherapy, we don’t have any fabulous biomarkers.
Dr. Powles: I agree with that. Sia, at the same meeting and actually at AUA and going back we discussed actually at ASCO GU together. There is a story evolving around the TAR program and there’s TAR-200 and TAR-210. I think that has the potential to be transformative. Do you want to just talk a little bit about what’s going on with that program in non-muscle invasive bladder cancer and some of the ongoing trials and how it could change them?
Dr. Daneshmand: Absolutely. Yeah. Let’s talk about TAR-201 first because that was the first agent that was sort of put into trial. This is a completely novel delivery mechanism into the bladder. We’re used to putting any kind of solution in the bladder. It’s always the same thing, 1 hour once a week for 6 weeks. No matter what we put in, that seems to be the recipe. We’ve gotten good response; BCG response rates are great. This is a novel delivery mechanism. This is what they call a pretzel that’s placed inside the bladder with a catheter. It goes in sort of straight, it has a nitinol wire. Once it enters the bladder, it maintains a pretzel shape. This thing is filled with little gemcitabine tablets that dissolve and elude the drug over a time period into the bladder.
You’d think, well gemcitabine doesn’t really have that much activity in non-muscle invasive bladder cancer. The prior phase 2 and 3 trials have shown like 20% response rate in non-muscle invasive bladder cancer that are BCG refractory. However, when you think about it, the sustained response is really the key. Gemcitabine is a very active drug, as you all know, in bladder cancer. Initially we had a phase 1 trial just to see, this was in 2016, with a company called Taurus that designed the pretzel, put it inside the bladder. We did it as a neoadjuvant sort of window of opportunity trial and we put it in, and we actually saw results. This was visible results with the pretzel, very well tolerated. Obviously this has moved on to the various trials they now called the SunRISe trials 1, 2, 3, 4 in the various states of bladder cancer. The most exciting one so far and the one that’s been presented numerous times at the various meetings is the SunRISe-1 trial, which is the TAR-200, again same pretzel, it’s gemcitabine tablets, BCG unresponsive disease.
I presented the initial results of the AUA just in May [2023], and at ESMO they had the updated results with 30 patients having a 77% CR [complete response] rate. That is more than anything we’ve ever seen in non-muscle invasive bladder cancer so far. There are other agents that are coming along with combination therapies that are similar, but this is really exciting for a device that is placed in the bladder that is easily retrieved and very well tolerated. The AEs [adverse events], if you look at it, grade 1/2 stuff we’re all used to with urinary frequency, irritated voiding symptoms; 77% CR at any time. There are 6 patients who are over now a year in treatment, they’re tolerating it very well. They now get it quarterly. Initially it’s every 3 weeks and now getting it quarterly. I think no question, this is going to have a place in the management of bladder cancer, in non-muscle invasive bladder cancer, and it’s going to be part of our armamentarium.
It’s easy to place, easy to learn, easy to remove, and the patients really like it so that’s one. We’ve been talking about erdafitinib, and we’ve been following this very carefully, and like Petros said, we had the approved 302 trial with infigratinib, another selective FGFR3 class inhibitor. In non-muscle invasive bladder cancer, we have about 30% FGFR alterations. In low-grade disease it’s actually 60% to 70% alterations. It’s natural to think, “Okay, somehow we got to get erdafitinib into the non-muscle invasive.” Initially we started out with the oral agent. I actually was given it myself, learned about all the toxicities.
Dr. Gupta: I’m impressed.
Dr. Grivas: Impressive skills by Dr. Daneshmand of course.
Dr. Daneshmand: No, thank you. I’ll hand it back over to you guys. We saw responses. This is a cohort of THOR-2 trial, the cohort 3 with low-grade cancer we discussed at ASCO GU, oral erdafitinib for a non-muscle invasive bladder cancer we actually saw responses. We saw these tumors go away. Amazing results. Very few patients, but amazing results like within 6 or…
Dr. Powles: There was that interesting part where you actually left the tumor behind and gave the whole tablet.
Dr. Daneshmand: Exactly.
Dr. Powles: I thought that was really very innovative. But it’s not the easiest tablet.
Dr. Daneshmand: No.
Dr. Powles: It’s not like enzalutamide.
Dr. Daneshmand: Exactly. Yeah.
Dr. Powles: It’s like a proper drug.
Dr. Daneshmand: Absolutely. I got to learn that the hard way. We’re using 6 mg, which is a little bit less than the 8 or 9 mg that you use for metastatic disease, but nevertheless we saw the nail toxicity, hyperphosphatemia, and the skin changes and things like that. But nevertheless, it was active in both low-grade and high-grade disease. Cohort 1 of THOR-2 trial was a high-grade disease. It’s natural for that to move into now an intravesical delivery system and that’s exactly what they did with the TAR-210 study. Now they have the erdafitinib tablets within the pretzel and we’re using it in, again, multi-cohort trial. It’s multiple cohorts in both high-grade disease as well as low-grade disease. Again, the preliminary results are super exciting and some of it was presented at ESMO.
Dr. Gupta: I think it’s one of the best innovations in urology, for a non-urologist.
Dr. Powles: Isn’t it crazy when you look back and you say, “Well, you put something in and wank and you can run around.” It just seems like a logical next step, I think potentially transformative as well.
Dr. Daneshmand: I think so too.
Dr. Gupta: You think they can put pretty much anything in that pretzel?
Dr. Daneshmand: Right.
Dr. Gupta: ADCs [antibody-drug conjugates]?
Dr. Daneshmand: I think so. I think in the future it’s all about the sort of biochemistry of how you’re going to get the drug and the urine to elude the drug within a certain time period and not have the toxicities. Fortunately, these drugs so far are not very toxic to the actual normal urothelium. We actually see this, we’re scoping these patients in 3-week interval, 6-week intervals. Really we don’t see that irritation, inflammation that we are so used to seeing with BCG, with mitomycin, and other intravesical.
Dr. Grivas: It’s very interesting, to your point Tom and Sia and Shilpa, how much we’re learning about drug delivery, right? Gemcitabine is the same drug we used for like decades. With the potentially optimal delivery, reaching the target, maybe sustainability of release, maybe the pH in the environment. It’s hard to tell, but the delivery of the drug may make a big difference. To your point, Sia, the 77% response clinical complete response rate was based on independent review committee. It was 80% based on investigator. It was a small sample size to your point with short follow-up, but very promising, potentially transformative. I’m excited to see what other agents can be delivered intravesically. The patients, to your point, Sia, are used to the intravesical delivery of the agent, even if it’s solution or now a pretzel.
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