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Ashish Kamat: Hello, everybody, 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 distinct pleasure to welcome back to the forum Professor Bogdana Schmidt, who is from the University of Utah. Bogdana, thank you so much for joining us today.

Bogdana Schmidt: Thank you so much for having me. It's always a great treat to speak bladder cancer with you.

Ashish Kamat: Hey, so we had a nice little interview session at ASCO GU in real life, in person. And, of course, you gave this really phenomenal talk at the plenary session on the changing world of non-muscle-invasive bladder cancer. So it's great for you to be able to join us today and relive that plenary talk that you gave. And I'm really looking forward to hearing what you have to say. So take it away.

Bogdana Schmidt: Certainly. The world of non-muscle-invasive bladder cancer is changing. I'll try to do this topic justice by focusing on some fundamentals, some definitions, where we are today, where we're heading, and, hopefully, what we'll be able to offer our patients.

As you know, most bladder cancer is diagnosed in the non-muscle-invasive space. Tumors are typically identified on imaging and cystoscopy and staged based on transurethral resection. And when you get the resection, you're able to stratify the patient into low, intermediate, or high risk.

Low-risk patients tend to have predominantly low-grade solitary tumors. High-risk patients tend to have large, recurrent, or aggressive high-grade tumors—Ta, T1, CIS, variant histology. And intermediate risk, per the AUA Risk Stratification System, has large, recurrent, or multifocal low-grade tumors and high-grade Ta tumors that are smaller than 3 centimeters.

The European and IBCG stratification makes low risk just low-grade tumors; high risk, all high-grade tumors, so all Ta’s, T1s, CIS, and variant histologies. And intermediate risk is just low-grade tumors. They can be recurrent. They can be large. They can be multifocal. But they’re all low grade.

And then the treatment paradigm depends on how many risk factors patients have. So for every risk factor, this can change the treatment. For patients who have zero risk factors, after they have their resection, they can have a periop chemotherapy, typically gemcitabine now, but it could be mitomycin. And you can consider office fulguration and observation where appropriate, but you don’t go on to offer these patients any adjuvant therapy.

Intermediate-risk patients with one to two risk factors get their TURBT and single dose periop. And the recommendation is that these patients undergo intravesical chemotherapy. If they fail that, they can receive BCG.

And for high-risk patients—three risk factors or greater—after TURBT, these patients are offered induction BCG with maintenance up to a year. And certainly, if that doesn’t work, you can trial intravesical induction therapy.

But BCG has really been the cornerstone of high-risk non-muscle-invasive disease for over 50 years. And this is a pretty laborious journey for a patient. They undergo resection. They have induction BCG for six weeks. They have cystoscopy maintenance every three months for the first two years, maintenance BCG—three-week courses—again, cystoscopy, again, maintenance, and so on and up until 36 months.

But we all know that BCG is not perfect. There are the general side effects that patients experience. The treatment schedule is intense, as I just demonstrated. For some patients, this is undertreatment. For some patients, this represents overtreatment. There is no selection or targeting.

And we’ve all been plagued with BCG shortages in recent years, where we really couldn’t give our patients as much as we wanted, having to postpone, delay, or stop maintenance therapies or having to split-dose BCG. And we know that, even in the perfect setting, 30% to 40% of patients will experience recurrence and progression after BCG treatment.

Now, this is where things get tricky, and the terminology becomes important for all of the trials that we’ll allude to. But it’s important to keep in mind what these definitions mean when BCG doesn’t work and, more importantly, focusing on the definition of BCG-unresponsive disease, which is patients who are BCG refractory or BCG relapsing within six months of last BCG exposure. And these patients were highlighted to be considered for single-arm studies because the standard of care for BCG-unresponsive disease is radical cystectomy versus additional intravesical treatments.

And so this is where this definition came from. Patients with T1 at their first evaluation after induction BCG, usually the three-month, patients who have Ta or T1 within six months of adequate BCG, or patients with recurrent CIS within 12 months of adequate BCG. And adequate BCG is important. Patients need to have at least five of six induction doses plus two of the three maintenance doses.

And so patients who were able to do that—or, rather, recurred after meeting that definition—were able to enter some of these trials that we’ll discuss because their standard of care is radical cystectomy. But we know patients don’t want radical cystectomy.

This is one of the larger studies looking at patient treatments for BCG-unresponsive disease. And they had a cool concept. They presented patients with a scenario of time to radical cystectomy, what is your risk of progression to muscle-invasive disease, risk of experiencing side effects, and gave them the option of an intravesical treatment once a week for six weeks, an intravesical treatment once every three months, or radical cystectomy.

And you saw that 89% of patients never selected radical cystectomy as their preferred options. And their preference for the other treatments depended on how much time they could delay radical cystectomy, risk of progression, and how the route of administration went, whether it was the Q3 months or every six weeks, more like a BCG cycle.

And you can see here, from the way that these patients answered the questions, patients were willing to accept a 44% increase in the risk of progression and a 66% increase in the risk of serious side effects to delay radical cystectomy from one year to six years. So this is really tremendous.

And based on studies like this, and knowing what our patients want, we now have numerous agents in this space. We’re no longer in the 50 years of BCG. We have some novel delivery mechanisms.

We have immunotherapeutics; chemotherapeutic combinations, like gemcitabine-docetaxel; immunotherapeutics that are delivered intravenously, and now there’s work on a subcutaneous injection; immune-activated models like BCG, so something that enhances BCG; and different oncolytic virus activations. Now, I mentioned UGN-102 here. This is not approved for the BCG-unresponsive setting, but this is an interesting mechanism nonetheless.

So how do we make sense of all this? This space used to be super narrow, and now it has gotten really broad but still a little bit challenging. Well, we can focus on, again, what patients want—complete responses, durability of responses, does this delay radical cystectomy, how does the schedule differ from what they’ve already been experiencing, route, side effects, and we’ll touch a little bit on costs.

So here’s the menu. This is the trials that we’ve seen in this space, a mix of phase I to II to III studies. And I won’t spend a lot of time on this, but I do want to point out this complete response rate definition. This definition of complete response at any time tells you that, at any time point this drug was evaluated, what kind of success rates were we seeing.

And you’ll see that this varies somewhere between 40% to 83%. But when you look at the 12-month disease-free survival, meaning what does it look like a year later, you’ll see that some of this data is not quite mature and certainly not as robust as we’d like to see it.

Obviously, we mentioned the delivery is different. You have IV options, intravesical options. We have schedules that are different, more like a BCG schedule, once a week for six weeks, or once every three months in the case of nadofaragene. Certainly, the safety profiles are different but, overall, fairly well-tolerated.

And when you have such an array of options, you really need to figure out, Well, how do you sequence these drugs? How do we do this? So this is where IBCG really tried to come up with guidelines and recommendations in this setting, trying to focus more on the disease biology in this space, so separating patients—CIS plus/minus papillary or papillary-only disease—and looking at what order you should consider these patients for, still prioritizing that clinical trials in the space are ongoing. And if a patient is suitable for a clinical trial, you really should consider it prior to one of these newly approved options.

One thing I do want to point out, though, is, in these trials, you see that a significant number of patients did go on to cystectomy and did have muscle-invasive disease, something we know our patients obviously want to avoid. And if you look more specifically at the numbers of patients with T1 CIS, these more high-risk features, you’ll see that the absolute numbers in these trials were quite small.

And so you really have to take the data here with a grain of salt and apply it to your patient, not broadly but more specifically looking at, Does this actually represent my patient in this scenario, especially if the patient has a high-grade T1 tumor plus CIS? Because, even though these drugs are approved for that indication, the absolute numbers of those patients in these trials were quite small.

So I’ve mentioned some specific things, but I want to get into some bigger ideas because we focused on BCG for so long. I really don’t think that’s going to be the future. And it’s not just the shortages and the tolerability. It’s because it doesn’t work as well as we want it to, plus all of those other things.

I think monotherapeutics are unlikely to be the Holy Grail. There are some interesting combination chemotherapy options, combination immunotherapy options, possibly combinations of intravesical and systemic drugs. Certainly, if they demonstrate greater efficacy and durability, people will be more interested in this space.

And I mentioned BCG is non-selective. It’s overtreatment for some and undertreatment for others. And being able to select patients for treatments really would change the game here.

So I want to bring a little bit of data that’s different to the slide, stuff that’s not yet approved but is interesting. This is the GEMDOCE trial. This is for BCG-naive patients looking at using the combination gemcitabine-docetaxel. This is a small trial, 25 patients, predominantly papillary. This was done during a BCG shortage, so patients were basically protocolized to receive this.

And you’ll see they had 100% response at three months, 92% at 12 months. This is greater than what we saw in any of those trials. But again, this is BCG-naive. That was BCG-refractory—not quite the same thing.

This is a different trial. This is GEMBCG, a pretty intense treatment schedule. You’ll see here that it’s gemcitabine, 2,000 milligrams twice a week, and then BCG weekly. This is a different combination of these two agents.

And this was trialed in patients who are BCG-exposed, so patients who received BCG but didn’t meet that strict definition of having had five of six induction doses plus two of three maintenance doses. And you’ll see again here, 97% high-grade recurrence-free survival at six months, 85% at 12 months. These are very promising. Twelve-month cystectomy-free survival, 100%.

This is an example of a targeted therapy. So this is for patients who have an FGFR3 alteration, so papillary-only disease, BCG-unresponsive. And you’ll see, again, very small numbers. But 77% of recurrence-free survival at 12 months is quite impressive. Median recurrence-free survival not reached in the therapy arm.

And this is something about making the treatments more specific or, rather, How do we select for the right treatments? This is an AI computational histology model that uses H&E slides and has developed a signature to predict response to BCG. They have data suggesting that, in some patients who don’t have that BCG response signature, GEMDOCE could provide an improved response outcome.

Again, we don’t have a lot of ways now to distinguish which patient’s going to do better with one versus the other. And having more of these models that could help guide these treatments would really make a big difference.

So in conclusion, non-muscle-invasive bladder cancer management is absolutely evolving beyond our paradigm of TURBT and BCG. There are new intravesical therapies. There are going to be new intravenous therapies, potentially sub-Q therapies. There are going to be new combinations. And our job is to really focus on, What do our patients want, and how do we use these new agents to better deliver care, make it more biomarker-driven, risk-adapted, and patient-centered so that we could ultimately reduce recurrence and progression in this space?

I want to acknowledge folks who have generously shared some of their slides with me so that I could make this presentation. And I really appreciate your attention. Like we said, this is a lot more than 12 minutes can do.

Ashish Kamat: Thanks so much, Bogdana. You covered a whole bunch of stuff in a short time. And we really appreciate this. As you concluded, this deserves much more than 12 minutes.

And we were fortunate enough to actually share more than 12 minutes at ASCO GU in person in San Francisco, where we went into a lot of Q&A and a lot of more in-depth discussion. And I’d love for the audience to be able to reference that, so we’ll put that link down here for the UroToday audience. So thank you again for spending time with us.

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