Bogdana Schmidt: Thank you so much for having us.
Ashish Kamat: So there's a lot happening in bladder cancer as always and one of the things that's happening that I'm really excited about, no bias, is having you guys debate at the IBCG Forum. So we have a lot of drugs that have been approved, some not approved, used for BCG-unresponsive bladder cancer patients. And let me start with you, Bogdana. How do you process the information that you have today when you're counseling patients and recommending a treatment?
Bogdana Schmidt: Thank you for the opportunity to discuss this. This is a real conversation. I think that first decision I have to make with this patient, is this a patient that I truly believe needs to go straight to cystectomy or is this a patient where we have room to think about bladder sparing options? And that in itself is a complicated conversation.
But once you decide that this is a bladder sparing patient, then there's a lot of factors you have to take into account. I have to take into account the patient's ability to come for multiple visits. I have to take into account how many caregivers they have and how many people this is going to impact. I have to take into account what their bladder's willing to tolerate and how much lower urinary tract burdens symptom wise they already carry before I offer the next line. And then I have to think about what is my overall goal? Is it to try and eradicate this cancer completely? Am I going for complete response durability or am I trying to buy time and give the patient something that maybe won't get rid of the disease right away, but will make both of us feel like we're doing something until we figure out the next steps or the next line? So all of that goes into my decision-making for these patients and unfortunately it's seldom truly a 10-minute conversation.
Ashish Kamat: Yeah. It used to be we had nothing for these patients and now we have so many options. Shared decision-making gets thrown about quite a bit, but sometimes it's almost like the patient says, "Please just tell me what to do," and if that is factored in. And again, factoring a litle bit of best of what you're going to debate, right? Amanda, how would you tackle that question from the patient? "What's best for me?"
Amanda Myers: So I think shared decision-making is extremely important. And as urologists, our job is to present the patient with all the treatment options available. If the patient is asking me what they should do when I look at the data between the available FDA approved options and the guideline endorsed options, the efficacy is broadly comparable. The data we have is based on small heterogeneous cohorts of patients. We don't have any randomized head-to-head data. So we have to go beyond the efficacy and actually think about how is the patient going to tolerate this treatment? Is the treatment safe? Are they going to be able to stay on it? What does the treatment cost? And those things are going to matter when the patient's deciding what they're going to do.
Ashish Kamat: Right. Now we got out of the way what you guys actually do, which is great. You take patients' preference and considerations into mind. Now let's focus on the debate. So you go first, Amanda.
Amanda Myers: So my debate task is to argue that gemcitabine docetaxel is the de facto first-line option for BCG-unresponsive CIS. And I would say that this treatment, again, saying that all of these treatments have broadly similar efficacy, gemcitabine docetaxel is the de facto standard because it is been shown in real world data to be safe, tolerable. Despite it not having FDA approval, it's been widely uptaken. It's accessible. Urologists are familiar with giving intravesical chemotherapy, they feel comfortable giving with it and they believe the signal. And that's why it's so widely used, not only in the United States, but growing globally and being used across the world.
Ashish Kamat: And your rebuttal or counter to that?
Bogdana Schmidt: She already made my argument. She started by saying that we have all these options and we have to talk to each individual patient about what they need. So I really don't think we have a first line. I think gem/doce is great. It is safe. It is easy. It is cheap. That's a really big advantage point compared to all the other new drugs we have. But it's also the weakest data we have because it is retrospective. And the others are FDA approved prospective trials with, like you said, similar efficacy most of the line, but that data's more reliable. It's better data. It doesn't have as many patients lost to follow up. We know exactly what the interruptions, disruptions, terminations were because that data was prospectively collected for that.
So gem/doce has its place. So does nogapendekin. So does nadofaragene. So does pembrolizumab, it's the smaller space in my practice, but it is an FDA approved option for patients. Gem-iDRS, also approved, and I'm sure we're going to get cretostimogene approval sometime soon as well.
So it's a little bit of a rags to riches, right? We went from nothing, now we have this wealth of options. And really the hard part is figuring out where do we go first? I think that's where shared decision-making is going to win out. Each individual patient is going to have a different starting point. Until somebody wants to do a trial of all of these head-to-head, and please somebody give us money, I'm happy to run it, we're not going to know what the first line de facto standard is. Everyone's going to pick their own.
Ashish Kamat: Yeah. I think since we recommended and the FDA adopted the BCG-unresponsive single-arm study paradigm, we've had this explosion of drugs and it's hard to make sense without head-to-head comparisons between the agents. But Amanda, is Bogdana correct when she says that the data collected in the single-arm prospective studies is truly better than the retrospective data with gem/doce?
Amanda Myers: Prospective data does have its advantages. With gemcitabine docetaxel, we actually have some prospective data now coming out. We have early reports of 19 patients with BCG-unresponsive CIS collected prospectively. High-grade recurrence-free survival at six months in that group was 75%, which is exactly what we saw on the retrospective data, and those trends are carrying out with time. We also have a prospective study of gemcitabine docetaxel for BCG-unresponsive that we started at University of Iowa and we just enrolled our first two patients this month.
Ashish Kamat: Again, Bogdana, when you talk about the different drugs that are available, right? Absolutely agree with you. There were studied according to FDA paradigm, they were approved according to the FDA paradigm, but when a patient asks you to counsel them on drugs, in your practice, again, leaving the debate a little bit on the back burner, do you actually factor in the FDA approval status or do you have a discussion with the patient based on other parameters?
Bogdana Schmidt: No, I think other parameters. The FDA approval is purely for how much do I trust this data? And I agree with Amanda, certainly more data to come will increase the trust we have in gem/doce for comparator's sake. But I don't think the FDA approval necessarily moves the needle for me. It's more so the fact that this is data that we know we trust. Nadofaragene has five-year data, the rest of them do not. So there's a lot of nuance in the data.
Ashish Kamat: And I don't want to make anyone's case for the debate, which I'm really looking forward to, but let me ask you a very provocative question, and then Amanda, you could chime in as well. So two things. We hear from people in the community that they don't want to use gem/doce because it doesn't pay as much and it's burdensome for the practice to have a patient for three hours in the clinic. Amanda, you've done some work on cost-effectiveness in this space, right? What's your answer to that allegation that it is cheap, it doesn't make the practice money and it costs a lot of time? How would you educate or address that concern?
Amanda Myers: So I think that the cost is very important because patients care about the cost. BCAN recently published the New Faces of Bladder Cancer report and in that, 20% of patients experienced a financial burden. And that's higher in females and it's higher in patients under the age of 50. And concerningly, some patients actually were either delaying or not undergoing recommended therapy because of concerns about cost. And patient adherence to treatment is the utmost importance and we need to continue to have these conversations around cost to really improve the clinical decision-making when we're talking with policymakers, insurance companies, and administrators to find a way to have cost-effective options be available to our patients, whether it is in the community or in academic practice and looking at ways in which we can overcome these hurdles to provide our patients with cost-effective treatment options.
Ashish Kamat: And Dr. Schmidt, and of course, Dr. Myers, you both are part of the International Bladder Cancer Group, which by definition is an international organization, right? So when you're talking to colleagues across the globe in places where there is no access to drugs, how are you advising them to think about the different options that might be available in their country soon if they're approved in that country when it comes to sort of a global utilization aspect?
Bogdana Schmidt: Yeah, I think that's a really important thought. I think that you can only offer your patients what you have and you have to think about what's available in your workplace, what your payers are going to do. You don't want to get into a situation where some patients on a nationalized system can only get one drug and some patients with a private pay are going to be able to afford another drug. And you as a clinician, that can be a very challenging decision-making point if that's truly coming head-to-head. But I think that in the absence of tremendous clinical benefit superiority of one system over another, you have to work within your health system.
Ashish Kamat: Yeah. I think having all these drugs available, approved, even off-label, gem/doce or even hypothermic mitomycin in certain countries, is great for patients, right? Because now we have choices, we have options. There's no biomarker. I would love if there was a biomarker that would help us choose which drug for which patient, but in the absence of a biomarker, it's all these clinical variables, social variables, patients' preferences. Can they come every three months? Can they come every week, twice a week? All of that is something that factors in. And I think that's where the art of taking care of bladder cancer patients is even more important today than it ever has been, right? You can't just plug these into an AI algorithm and have it spit out, "This is the best for this patient," because there isn't that answer.
We could chat about this forever, but I think we'll close, but in closing, I'd like to give you guys the last word. So whatever you want to say, whether it's debate-based or it's just general principles of BCG-unresponsive disease. Amanda, you go first.
Amanda Myers: I would just like to close by saying, I think we've spent a lot of time focusing on, we do need biomarkers, and we spend a lot of time focusing on patient preferences and the complete response rate for these drugs. But moving forward, I think we need to think beyond that and actually think about the progression risk to the patient. When you look at the BCG-unresponsive historical data, progression rates were very high. And with some of the newer agents, we're seeing very low rates of progression being reported out. Are these drugs truly changing the disease biology and the trajectory of the disease beyond the patient recurring or are we just delaying cystectomy? And I think understanding that was the next step for how we're going to decide what treatments to use for patients.
Ashish Kamat: Very good point, but I would ask you to take credit for the reason some of the progression rates are going down, both of you, because I think urologists have gotten better at selecting patients, doing better resections, better scopes. I don't think it's necessarily the drugs that are doing it, right? The natural history has evolved over time. So great point, but I think you should take some of the credit for that. And Bogdana, your closing statement?
Bogdana Schmidt: I'm going to take a lot of credit for the fact that we're in a much better place in urology, in bladder cancer space, because of all of these drugs, because of people doing great research, whether it's cost-effectiveness or patient preferences, like the CISTO study, we can have more informed conversations with our patients. And to me, all of that's exciting. Let's keep going. Let's do more.
Ashish Kamat: Excellent points. Thank you so much for taking the time.
Bogdana Schmidt: Thank you.