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Ashish Kamat: A warm welcome to all of you from the UroToday studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. We're live in San Francisco at ASCO GU 25. And it's a pleasure to welcome to the stage Bogdana Schmidt. Thank you so much for taking the time and joining us today.

Bogdana Schmidt: Thank you so much for the invitation. Happy to chat.

Ashish Kamat: So you're going to be chairing the session on non-muscle invasive bladder cancer. And essentially, we're going to hear from you and the panelists as to what's new. So what is new?

Bogdana Schmidt: Well, there's a lot that's new. I think that the menu used to be short and uninteresting for a very long time. And now, there's a plethora of options in all of the spaces—in the BCG-refractory space, in the intermediate-risk space. There's a lot of new mechanisms, a lot of new drug delivery models. So everything is new.

Ashish Kamat: So what about the things that are coming in excites you the most?

Bogdana Schmidt: I think the most exciting things to me are things that make things easier for our patients. So patients care about how effective their treatments are, but they also care about how convenient their treatments are. So all of the models that are looking at changing the route and delivery schedule are interesting to patients.

So talking about TARIS, the gemcitabine pretzel, slow release once every three weeks, talking about anything that is delaying the schedule, so nadofaragene firadenovec every three months. Anything really that's going to make this more convenient to patients, that doesn't rely on multiple hours every week in the doctor's office, travel, cost, inconvenience.

Ashish Kamat: Yeah. And patients look at obviously efficacy and side effects and also convenience like you talked about. But I think the main thing that a patient comes and asks you, I'm sure, is “Dr. Schmidt, what's the best treatment for me?” So today, if you have a patient come into your office that has high-risk non-muscle invasive bladder cancer and says, “What's the best treatment for me?” Is it still BCG? Like what are you telling your patients?

Bogdana Schmidt: Yeah. I don't think it's still BCG, but I'm not sure that we all have the access to all the things that are probably going to be better than BCG. I think within a year or two, we're all going to agree that it's probably not BCG. But right now, a lot of places in the country don't have access to BCG. So BCG isn't an option for those patients. Gemcitabine/docetaxel is available, cheap. Most places that are academic can do it. Most places in the community don't do it because it's at least two-hour visits for patients, and it's a lot of staff time, room time. That's hard for patients to access.

I think the stuff that's interesting to me are some of the combo trials that we've already seen coming out, meaning using an intravesical agent and a systemic agent. They might show more durability, maybe better upfront efficacy—to be seen. But none of those are available yet. So if you're asking me right now, today in my clinic, if I have a patient who's high-risk coming in, if I have BCG, they're getting BCG. If I don't have BCG, they're getting gem/doce. And I'm waiting for all the other stuff to come in.

Ashish Kamat: Yeah, so that was a very provocative statement you made. And I agree with you in the sense that I think we need to do better than BCG. But as of today, the bar that BCG sets is really very high.

Bogdana Schmidt: Yeah, and the comfort that we have with it. We can tell our patients what to expect. Nothing's going to pop out really that we haven't seen over the 50 years' experience. The side effect profiles—we know how to manage it. We know what to expect from it. We know how to counsel our patients. I agree that the bar is high. But honestly, I think the bar is not high enough, in the sense that we've done this for 50 years and haven't made much progress. I think that yes, we have to answer to a high standard, but I think it's out there.

Ashish Kamat: And that brings me to what I was going to ask you: the [INAUDIBLE] treatments—taking an IO and adding that to BCG. How do you think that you and your patients are going to be able to balance the toxicity of a systemic agent with the efficacy, and what percentage increase would you want to see to be able to justify that?

Bogdana Schmidt: I love that. I don't think anyone truly knows. I personally am very cautious about the IO combinations. I think intravesical disease should be treated with intravesical treatments. But if we can truly see a response that's greater than, let's say, 70%, so we're talking about 90% at 12 months, and that patient only needs 12 months of treatment—yeah, I think it's worth it. I think it just depends on how efficacious they are.

And of course, I think we all have a lot to learn in the urology setting of how to manage these side effects. I think our medical oncology colleagues have been handling the IO side effects for at least most of us in academic practice. And so we'll really need to make sure we are not missing presentations of autoimmune symptoms and side effects and doing our patients a disservice by not getting them treatment as soon as they need it.

Ashish Kamat: Right. And clearly, POTOMAC and CREST and ALBAN have not read out for so many years because the events have likely been low.

Bogdana Schmidt: Yeah.

Ashish Kamat: But CREST just had a press release, so excited to see what the data there shows with sasanlimab and BCG.

Bogdana Schmidt: Yeah, absolutely. And that one's interesting too because it's not intravenous. And so patients may find the subQ formulation easier, faster from a patient convenience standpoint. But again, it all depends on the efficacy. It all depends on the adverse event rate. It's either going to be worth it or it won't.

Ashish Kamat: Moving into the BCG-unresponsive space, I mean, there's been an explosion of trials and drugs. And you've been part of the BCG effort to try to help sequence those agents. What's your sense now, today, with the approved drugs—let's not talk about them for just a second because we have a lot of data on those—but the trials that are currently ongoing? We've seen updates from TAR-200. We've seen CG, cretostimogene grenadenorepvec. We're also looking at enGene and all the others. My personal sense is that all of them should be approved if they work so patients have the choice. But how do you potentially think about sequencing these drugs in your patients?

Bogdana Schmidt: Yeah, I think that that's going to be really important. And I think groups like the BCG One will play a real role in getting expert consensus panels to help physicians make these decisions. And I agree with you—I do think that we should be going towards approval of all of the ones that are safe and efficacious, as opposed to limiting the pipeline. Because I think they all have a role to play. The Taris, obviously, the delivery mechanism is different. The Q3-week schedule might be preferred by some patients. Cretostimogene grenadenorepvec is a little bit of a longer setup in the clinic just because of the wash that the patients have to have, just a little bit more time—not as much time as gem/doce.

And enGene, I think we definitely need a little bit more data there, but it's a lot easier for safety and handling for some practices. Because for enGene, you don't need high-capacity freezers, all the extra storage. That one is so much easier to handle. Some places will choose that just because they can use it and get it started quickly.

To get back to your question about how we're going to sequence these, I think cross-trial comparisons are going to be really hard in this case. The patients—everything's going to be just a little bit different on how many of what type of patient with what pathology they enrolled. But I think that looking at the eventual outcome of delaying cystectomy—if that's the goal of the patient and the adverse event profile is favorable—then you start with the one that gets you there first. And then you move on to the next one. And you still have to keep talking about cystectomy with these patients, because you don't want to miss the window where you can still cure the patient.

Ashish Kamat: Yeah. I think that's an important point for our listeners, that we don't want to miss the window of opportunity for cure. But if you go back 10 years, when the whole BCG-unresponsive paradigm was in some ways proposed or being thought about, you always thought that radical cystectomy is your control arm. And because we can't use that as a control arm, let's allow single-arm studies—great. But we were also hesitant to allow pharma or investigators to re-induce patients if they didn't respond at three months. We've now learned over time that if you don't have a response at three months, it's likely not unsafe. So we can do another challenge. But in your sense, how many rounds of treatment would you allow or recommend to your patient before you're like, “No, at this point, you've got to have your bladder taken out”?

Bogdana Schmidt: I think it depends on the patient. I think it depends on their disease and their eventual goal. Now, when you're looking at patients that are T1, LVI, there are very few of those patients in all of those arms in all of those trials combined. And so I think it's very hard to prognosticate in that patient population and say it is safe to go round one, round two, re-induce, etc., etc. So that would be the patient population where I probably would hesitate to do more than one or two lines of treatment. I think that we have enough data to suggest that those are bad oncologic actors, and we need to be treating them aggressively.

If you have an older patient who otherwise has a pretty good quality of life, who just has CIS that maybe keeps coming back but not much more in volume, one or two spots here and there—imaging looks good, everything else is OK—I might be able to push the envelope there a little bit more, counseling the patient, obviously making sure that's what they want and that it's a priority of theirs for bladder sparing. I think that there might be a little room to go a couple lines of therapy, monitoring carefully, continuing surveillance.

And I think that we might have more clues with urinary-based markers in the future too. We don't have that today, but that's my hope. My hope is to be able to figure out which of these patients really need to move on to more aggressive therapy and which of these patients are going to linger in that state of recurrence without progression for a while.

Ashish Kamat: Right. I mean, again, bladder cancer is such a chronic disease. If you can make it even more chronic, not at the cost of function or cost to society, that'd be great for our patients.

Bogdana Schmidt: Yeah.

Ashish Kamat: This is really a great conversation. Any closing thoughts for our listeners?

Bogdana Schmidt: I think it's a really exciting time for bladder cancer. I think that when I started in this career a very short time ago—and even then, we were still not hearing about nearly as many avenues that we were going to be treating bladder cancer patients with. We were looking at one-size-fits-all therapies, trying to make them more tolerable. And I think within the next five years, it's going to be different. We're going to be trying to customize therapy to the patient's disease, to the patient's goals, and hopefully, obviously, prolonging their quality of life and not limiting their quantity of life by going too far with all these new incremental projects.

Ashish Kamat: Yeah. A very, very, very good message. I mean, we've got to keep in mind, ultimately, quality and quantity of life—not one versus the other.

Bogdana Schmidt: It can't be one versus the other.

Ashish Kamat: Absolutely. Absolutely. Well, speaking of quality and quantity, thank you so much for taking quality time and spending it with us.

Bogdana Schmidt: Thank you so much. This has been great.