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Sam Chang: Today we are fortunate to have Dr. Karim Chamie, Professor of Urology at UCLA, and really a true pioneer and true scientist when it comes to urothelial carcinoma. He's done an extensive amount of research, and he was actually involved in a new session at the AUA 2024 looking at trials in progress that the AUA highlighted as important trials, currently enrolling patients in the evaluation at different stages of urothelial carcinoma. Dr. Chamie was actually chosen as one of the moderators of this session and was able to review all of them, help comment, and ask questions on all of them. So we're quite fortunate to have him here. Karim, thank you so much for spending some time with us, and I think you have some slides that you want to share with us.

Karim Chamie: Absolutely. Thank you, Sam. It was an honor. It was a blast. I think this was a really innovative approach that the AUA took on in discussing some of the new trials that are in progress, and I think it's important that we continue to highlight them. It was nice to see that it wasn't just urologists that were in the audience. You had key leaders, key opinion leaders in the field, but also representatives from pharmaceutical companies, who weigh in and talk about some of the concerns and some of the questions available for patients with bladder cancer. I thought that was really kind of cool. And to put it in the product theater, I think it was kind of nice.

So let me go ahead and share my screen. I wanted to highlight three different studies. And I think it's important to talk about the fact that there were multiple trials I could have talked about today, but I kind of want to limit it to three. And one is intermediate-risk, one is high-risk BCG-naive, and the other is muscle-invasive bladder cancer. So for the abstracts that I'm not presenting, I hope you don't take offense to it, it's just, I wanted to kind of diversify the discussion today.

So the first study that I wanted to talk about was the MoonRISe-1 trial. It's a Phase III trial of a TAR-210, which is an erdafitinib intravesical delivery system. It's the pretzel system, but instead of putting intravesical gemcitabine, they have intravesical erdafitinib, which is an FGFR inhibitor. FGFR inhibitor, for those that don't know, is an FDA-approved drug that's used for advanced urothelial carcinoma for people who have failed prior systemic therapies, and they have locally advanced disease, and they have either mutations or alterations in FGFR. And what they did is, they're targeting a similar audience, but instead of looking at those with locally advanced disease, their focus is on intermediate-risk, primarily non-muscle-invasive bladder cancer.

The reason this is important is because I think we tend to underestimate the amount of FGFR expression in bladder cancer. Obviously, as the disease becomes more advanced, it becomes less common. But in upper tract urothelial carcinoma and in non-muscle-invasive bladder cancer, it's by far the most common alteration mutation we see. So it's important that we talk about it, and I think it's a really tangible target here.

So this is an open-label, multi-center Phase III randomized trial. And here they're evaluating TAR-210 versus the intravesical chemotherapy of choice. And here they've either used mitomycin C or gemcitabine, it's intravesical. Patients have to have confirmed low-grade disease that's either recurrent or primary, or either multifocal, or if it's greater than three centimeters, but they have to have the FGFR3 alteration, either mutation or fusion. And they identify it through either a biopsy, in which the tumor would be resected and sent off for analysis, or this urine cell-free DNA technology. And there seems to be a significant amount of concordance between urine cell-free DNA and biopsy. So it's kind of innovative, I think, and it's kind of cool. Right now, it's a companion diagnostic, but I think in the future we're going to be able to use it, not just for people that we plan on giving FGFR erdafitinib to, but also for other kinds of patients, to kind of risk stratify. Like, is this someone who has tumor type A versus tumor type B? Are they more likely to respond to immunotherapy, or are they more likely to respond to erdafitinib or other intravesical agents?

And here, they're going to have 540 patients, and they're going to be randomized in a one-to-one fashion. Where they're going to get TAR-210, which is the pretzel, with erdafitinib every three months for about a year, or intravesical chemotherapy of either mitomycin or gemcitabine for four to six induction courses, followed by maintenance therapy, provider's choice, of six months to a year.

Their primary endpoint is disease-free survival, which is defined as randomization to the first documented recurrence of any grade non-muscle-invasive disease, disease progression, or death from any cause, whichever occurs first.

So this was a really nice abstract that was presented by Roger Li, and I think this is important, and I think it may change the landscape in the management of patients with intermediate-risk low-grade non-muscle-invasive bladder cancer. I think that we already have another drug that's potentially getting FDA approval with UroGen's 102 platform, where it's an intravesical mitomycin delivery system. So I think this adds to that.

The other is one that you are familiar with. This is the one that you presented, Sam. It's the SunRISe-3 trial of TAR-200 plus cetrelimab, or TAR-200 versus intravesical BCG for patients with BCG-naive non-muscle-invasive bladder cancer. Here, this is an open-label multi-center Phase III randomized study that's assessing the efficacy and safety of TAR-200 plus cetrelimab, TAR-200 by itself, or BCG in patients with BCG-naive non-muscle-invasive bladder cancer. Again, patients have to have histologically confirmed BCG-naive non-muscle-invasive bladder cancer. They would be excluded if they've received BCG in the last three years, but if it's been more than three years since their last treatment, they're allowed in. And this is kind of nice because they allow patients with TA, T1, and CIS. So it's not just limiting patients with CIS-only disease. If they have papillary disease, they have to have the tumor completely resected prior to randomization.

And here, they're looking at about 350 patients per arm, so about 1,050 patients. They receive either TAR-200 plus cetrelimab, that's group A, TAR-200 alone, that's group C, or BCG, which is group B. Those that are in the TAR-200, either alone or with cetrelimab, are dosed every three weeks for the induction phase, followed by every three months during the maintenance phase. Those that are randomized to BCG aren't quite getting the SWOG dosing. They get basically about almost two years' worth, so not out to three years, but they get a fair amount of BCG induction and probably two-thirds of the maintenance. The primary endpoint here is event-free survival from time of randomization to high-risk disease or first recurrence, or progression or any cause of death. For those that have persistent disease at six months, in the case of CIS patients, they defined progression here as an increase of stage from TA to T1, or from CIS to T1. Or if they develop muscle-invasive or metastatic bladder cancer.

So I think this is really interesting, especially in the context of BCG shortage, and potentially in the future, being able to further risk stratify patients who are truly high risk or not. So I think there'll probably be some ad hoc analysis of seeing patients who benefit from cetrelimab plus TAR-200, or TAR-200 alone as compared to BCG.

And then the final abstract I wanted to talk about is a study that Neal Shore presented. It's a pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with muscle-invasive bladder cancer. This is the KEYNOTE-992 trial. Here it is a randomized double-blind Phase III study evaluating the efficacy and safety of pembrolizumab 400 milligrams IV plus chemoradiotherapy, versus placebo plus chemoradiotherapy. So everybody's getting standard of care here with regards to bladder preservation.

Patients have to have histologically confirmed muscle-invasive bladder cancer with at least more than 50% being urothelial histology. Performance status has to be ECOG zero to two. No prior anti-PD-L1 therapies. Here, they're randomizing 636 patients in a one-to-one fashion to either getting pembrolizumab 400 milligrams IV or placebo every six weeks for about a year. So they give nine cycles, which is about a year's worth. Patients are all getting chemoradiotherapy, and it's up to the provider as to whether they want to get 5FU plus mitomycin C or gemcitabine. The radiation is conventional radiation, where they're getting 64 gray over a six and a half week period of time.

The primary endpoint is bladder-intact event-free survival. So they've defined it as time from randomization to the first documented occurrence of residual or recurrent muscle-invasive disease, nodal or distant metastasis, radical cystectomy, or death from any cause per blinded independent central review, whichever occurs first.

And I think this is kind of interesting in the sense that they're really highlighting the importance of bladder preservation. Because again, this is the point of the whole trial. I mean, you're looking at patients who are looking to preserve their bladder, and so I think it's important. So it's not just looking at disease progression or metastasis or death, they're actually looking at people who may end up still keeping their bladder, although that's being measured as recurrence or residual disease, but also measuring people who get their cystectomy out because they have, say, high-grade T1. So I think that's kind of novel in this trial design.

So I thought these would be three trials that would be interesting to talk about, because I think they span from earlier low-risk to muscle-invasive poor risk.

Sam Chang: Karim, excellent overview of three important studies. And just as you said, you could have picked any of the trials that were presented. I liked how you picked an example from different disease states within bladder cancer. So let's start with the last trial looking at invasive disease and the role of combination IO plus chemotherapy versus chemotherapy alone when combined with XRT.

I guess from your standpoint, if you look at these patients with invasive disease, at least at our institution, just the number of patients that we're actually advising or recommending discussions with our radiation oncologist has really increased. I think there's been a real shift away from cystectomy first, cystectomy second, cystectomy third, to understanding that for certain patients, this actually may be the preferred regimen, a combination of chemotherapy and radiation. And this study looks at the possible benefit of IO therapy in addition to that.

Tell me what's been going on at UCLA or on the West Coast when talking and counseling with patients with invasive disease.

Karim Chamie: Yeah. I think if you actually look at the demographics, and I think we're going to have to be forced to discuss bladder preservation. Because if you actually look at the demographics, the age-adjusted incidence of bladder cancer has actually gone down. If you actually look at SEER, the age-adjusted incidence of bladder cancer has gone down. Yet at the same time, the incidence of bladder cancer has gone up. So you're like, well, how could that be? How could the incidence of bladder cancer go up but the age-adjusted incidence of bladder cancer go down? And that's because we're diagnosing patients with bladder cancer at a later and later age. So I think we're seeing older and older patients, and a lot of these patients may not be good surgical candidates. And I think we're going to have to get accustomed to the idea that we're going to have to offer bladder preservation for patients that are probably not fit or suited to undergo major surgery like that. And so, I think that's important.

And then second, I think some of the things that we've learned from these BCG unresponsive trials are that a lot of these patients have recurrences, but many of them don't die, and many of them didn't go on to get a radical cystectomy. So I think as urologists, we're kind of becoming increasingly more comfortable in our skin as far as bladder preservation. Now that's for BCG unresponsive, but I think it's going to kind of diffuse and bleed into muscle-invasive disease. Because I think there's muscle-invasive disease where we need to do a cystectomy, neoadjuvant chemo and a cystectomy in a timely fashion. And there's potentially patients with a solitary muscle-invasive tumor that may be cured with systemic therapy and a maximal TUR. And obviously, we're seeing that data at GU ASCO with some of these novel systemic agents. So I think it's coming to our doorstep and we just have to learn the data. Have to see what the drugs are doing, and we have to talk to our patients about it, because I think that's the future because we can't do a cystectomy in everybody.

Sam Chang: I definitely think with the data that's coming out, with not only bladder, but if you look at kidney, and you look at other solid tumors, there clearly is a subset of patients that have a long-term, long-term, long-term response, even with advanced disease, in terms of maintaining a state of almost a chronic disease process, where things don't progress. And that for a period of time, you clearly can have long-term survivors. I hate to use the word cure, but clearly these IO therapies, as opposed to our cytotoxic chemotherapies, have resulted in some really long-term benefits.

Now, the difficulty would be identifying those patients a priori who really are going to be those responders. So that leads me then to the first study, to keep things out of order, and to keep you on your toes, is your description of the utilization of the urinary cell-free DNA in Dr. Li's presentation of MoonRISe, looking at the FGFR3 receptor, and looking at, actually, erdafitinib within the novel targeted release system, the pretzel that we used to call it. When you look at that data in terms of, you were talking about risk stratification and being able to determine perhaps who responds, who doesn't respond, tell me what you think the future will be with a urinary marker specifically, with that FGFR3 target?

Karim Chamie: Yeah. Obviously, the company's looking to use this as a companion diagnostic probably, for right now, it's for systemic therapies with erdafitinib. But I think in the future, if, and I think when, TAR-210 gets FDA approved, I think it's going to be used in that platform as well. But I think it's going to be used by urologists. Because I think we're going to be able to determine whether someone's tumor type is likely to benefit from BCG, or systemic immunotherapy, or whether someone's going to need intravesical chemo aside from the TAR-210 product.

So I think once we get more information, and once we kind of build this database of who responds to what, I think right now, we kind of know what they respond to, but that's in the muscle-invasive metastatic setting. There's no data on FGFR mutations in non-muscle-invasive disease, whether they're more likely to respond to BCG or chemotherapy, gemcitabine, or mitomycin, we don't have any of that data. So I think that's going to be really cool and interesting, and I think this is going to shed some light on that.

Sam Chang: Yeah. No, I agree totally. The early data with the Phase I trial looking at this erdafitinib pretzel and work that Dr. Li did out of Moffitt kind of shows that there are certain mutations that may be, in addition to FGFR3, may be predictive and may be able to be detected. And clearly, it's a combination of the changes found within the tumor as well as within the urine, and then subsequent therapy. And I also see it, in addition to what you say, I also see it as a possibility of two things, helping with diagnostics, perhaps even actually obviating the need for cystoscopy. And then secondly, to be able to deescalate treatment. You were talking about who's going to respond, for sure, I think that's going to be utterly important. But then also, who has responded, that we perhaps then could deescalate therapy.

Karim Chamie: Yeah.

Sam Chang: But then that leads to the second presentation that you gave, looking at SunRISe-3, looking at TAR-200, the pretzel, the targeted release system with gemcitabine. And before I forget, the one thing about the MoonRISe, about the TAR-210, the erdafitinib, I noticed on the dosing schedule, it's once every three months, once every 12 weeks. I mean, the decrease in morbidity associated with that. And then I was looking at the comparator arm of once a week for six weeks and then monthly treatments. Clearly, you could see some possible benefit, just in terms of the treatment burden, perhaps financial burden, all those things for patients. I just wanted to point that out.

But in looking at the TAR-200, the gemcitabine in the BCG-naive space, I think one of the things to really emphasize is, there are many trials going on now looking at this space, but many times in combination with BCG, or to treat patients that were exposed, but then give additional BCG in combination. This really is a look at one arm is BCG by itself, but then the other two arms are either the TAR-200 or the TAR-200 plus cetrelimab. As you look at this BCG-naive higher risk population, do you think it's just going to be one treatment, or do you think it's going to be a combination of some of these that have recently been approved in the BCG-non-responsive or unresponsive stage? What do you think ultimately is going to be the treatment of choice for someone? If I come in with a high-risk non-muscle-invasive bladder cancer, what do you think the treatment's going to be? Combinations? Is it going to include systemic? Is it going to be a combination of intravesicals? Kind of put your prediction cap on and tell me what you think.

Karim Chamie: Yeah. I mean, that's a great question, Sam, and you're asking me to predict what's going to happen in the future. I think what's going to first happen is, people are going to use some of these novel agents, right? I mean, so Anktiva N-803 plus BCG just got FDA approved. You have nadofaragene, you have pembrolizumab. And I think in the future, I have no doubt that TAR-200's going to get FDA approved, and CG Oncology's drug's going to get approved. It's going to get FDA approved.

I think the first area it's going to bleed into is patients who probably don't necessarily fit the criteria as far as CIS. You're going to have BCG-unresponsive papillary disease, and we think it's going to bleed into that disease space first. And then you're going to then hit other disease groups. So patients who don't necessarily fit the idea of BCG-unresponsive, they may have CIS, but not necessarily BCG-unresponsive.

And I think you're going to have more and more people being treated with some of these agents in the higher risk setting. I mean, some patients may have micropapillary disease, or they may have higher risk features, variant histology. I think that's where we're probably going to start seeing that utilized. Say, high-grade T1 with variant histology plus CIS, high-volume disease. That's probably where I see some of these drug combinations being used. But run-of-the-mill, I think a little bit of CIS with maybe TA or just CIS alone, I'm hoping that it's going to be monotherapy, because I think I wouldn't want to cause significant harm for these patients. Because when we talk about systemic therapy, if you look at the adjuvant trials, if you look at the CheckMate 274 trial, or some of these other trials that use systemic therapy, you still have 30% of patients that had to have discontinuation for a period of time. 18% of patients had to completely go off trial. So it's not benign.

And I think it's important to realize that some of these patients have toxicities that can be lifelong. I, at UCLA, have a number of patients who've received neoadjuvant novel therapies, and they develop hypophysitis, or they develop thyroiditis, and now they're on lifelong therapies, oral therapies, or they become diabetic. And it's just, we have to be cautious with those drugs, and I think we have to risk stratify, but I think it's going to be limited to patients who have more high-risk features.

Sam Chang: Yeah. I think that last kind of phrase that you spun there, regarding that understanding that risk stratification will be so important for these individuals, and you consider the risk definitely more so with those patients, honestly, who have a higher risk for progression. The recurrence risk is one thing, but that progression risk is what may ultimately drive, but then that's really determined by better risk stratification. And so, with scientists like you, helping us to better able to identify those individuals who truly are at higher risk, and then being able then to personalize therapy, will only improve the outcomes, as well as the choices for our patients with bladder cancer.

So Karim, as always, it's great touching base with you. I always appreciate your insights, because you really are that combination of both the scientist as well as the physician, and been able to treat so many patients and also start, actually, such important research. So thanks again for spending some time with us, and look forward to catching up again.

Karim Chamie: Thank you, Sam. It's been an honor.