Ashish Kamat: Oh, absolutely. A pleasure to be on UroToday at all times. And it's good for me to be on this side and not asking you the question, so this is great.
Zachary Klaassen: I know. We're just a little reverse role here. It's going to be fun. I think just to level set for our listeners, why is there a push for even considering BCG plus a couple of immunotherapy options in this space?
Ashish Kamat: Yeah. So again, we as urologists, uro-oncologists should really be proud of the fact that we have the best cancer immunotherapy, period. There is no other cancer immunotherapy that has come close to the success of BCG when it comes to non-muscle-invasive bladder cancer. That being said, it works so well that there's a global shortage. There's not enough BCG to go around. There's been a shortage in North America since 2014. And because of that, everybody's been trying to replace BCG or in many ways trying to see if, hey, can we get away without doing maintenance if there's a shortage? And also some of the older studies where BCG wasn't done appropriately, patients didn't really have that great a response. So people have tried, and rightfully so, I've been working on this as well, I'm sure you have as well, trying to beat BCG or replace BCG. So when that comes in, then of course we look to other immunotherapy and checkpoint inhibition is an obvious fit to combine with BCG as is IL-15. We're not talking about that, but NAI also is combined with BCG. But here we're talking about the IO, the checkpoint inhibitors.
Zachary Klaassen: Yeah. Well said. Just another background question, we've had three trials now, CREST, POTOMAC, and ALBAN. Can you just highlight general findings from these three trials that'll lead into our further discussion?
Ashish Kamat: Yeah, so those are three trials that were done using BCG plus IO. And the IO in the three trials were subcutaneous. There was Durvalumab, and of course there was Atezolizumab in the three trials respectively. The trials were designed fairly similarly in the sense that they had an arm where it was BCG two-year maintenance. They didn't do three years simply because they didn't think they would be able to get patients to get to three years, so two years. And then it was either a BCG induction plus IO or BCG induction maintenance and IO added to the induction and maintenance. What was remarkable was that the two positive trials, which is the Potomac and the CRES study that had the best study design. And we won't go into too much detail about the ALBAN. There were some study design issues there. Endpoints were different, but the two trials that had the appropriate study design, both came out with the same hazard ratio, 0.68. So when you add IO to BCG, you do improve upon the results of BCG provided you use maintenance therapy. In the arms that try to do away with maintenance, you show it essentially you can't do it with maintenance. So if you have BCG and one to two years of maintenance of IO added onto two years of BCG, you can improve upon that. But the hazard ratio of 0.68 Zach, is a little deceiving because when medical oncologists look at hazard ratios, they're used to looking at it in metastatic patients. When we look at it, we have to give patients all landmark analyses. So patients will ask us, "Hey, at one year, two years, what are my chances of being improved disease-free survival or recurrence-free survival from this treatment?" And that's in the range of five or 7%. So the benefit to the patient is not the same as the hazard ratio that has been reported in these trials.
Zachary Klaassen: Yeah, that's well said because I think patients don't understand hazard ratios. They say, "At 12 months, 24 months, what's my likelihood?" That's very well stated. And I think that's an important take-home point for our listeners. Moving to the JCO piece, you guys, it's a beautiful article. We'll link it to our discussion tonight as well. So people, I encourage them to read it. You performed an IPD analysis comparing the EFS or the DFS and the experimental arm. We'll talk about that arm first. What did you guys learn from that analysis?
Ashish Kamat: So Zach, the purpose of the commentary was twofold. I mean, number one, I was hearing a lot of things from people saying, "Hey, this is the new standard of care. Everybody should be getting IO plus BCG." And we in the international bladder cancer group, and of course a few of us came together and we felt, well, we need to put forward a commentary to address that, but also on the other hand, address the complete naysayers that said, "Oh, who cares if these trials were positive? We should never be talking about IO." That's not true either. Again, full disclosure, I think that the drug should be approved. That's a separate topic because I think they met their endpoint, they did a well-conducted study, patients participated, and I think patients need choices. So once the drug's approved, then we can decide how we want to use those. But with that in mind, within the commentary, we wanted to drill down a little bit and get a little bit into the weeds. And Bridget [inaudible 00:05:10], who is a coauthor on the paper, she's really good at doing these extracting the data from Kaplan-Meier curves and then reconstructing IPDs. So we looked at the EFS, DFS arms in the studies to see was there really anything that was very different based on the IOs? And the short answer was no. In the positive trials, the benefit was very similar. There were no new nuances that we gleaned. It was gleaned, of course, that you need to have maintenance BCG to get that benefit. But between the two arms or the two drugs, Durvalumab and [inaudible 00:05:46], there was not that much difference.
Zachary Klaassen: Right. And then you did the same thing for the control arms, which I think just shows how BCG's performing. And I think you had some really nice comments in your piece about that. So maybe just extrapolate on that control arm, similar analysis just using the controls from the three trials.
Ashish Kamat: Yeah, that was actually done, again, just like you, astutely mentioned to make a point because what happened is, and I remember this was in 2022, I was giving a plenary at one conference in Europe. And I just stated that, "Hey, Potomac hasn't read out even though it's supposed to two, three years ago, probably because the event-free survivals were focused on the old data and they haven't had enough events." And I got a bunch of calls from people saying, "How do you know this confidential information?" I'm like, "I don't. I was just making a common sense deduction." And that's what happened. So these trials were based on the old BCG data where 33% of patients progress, 33% in addition to that recur and only 33% of patients actually have a good response. That's not true today. So we wanted to look at these trials, which really kudos to the investigators, kudos to everybody that participated. This is a treasure trove of data of patients treated with BCG in the modern era. And when we did the IPD, we showed clearly that if you and I use BCG appropriately today Zach, and I'm not even talking three years, because these trials only looked at two years maintenance, you can get 80 plus percent event-free survival, and that's including recurrences, including persistent disease, not progression. Progression was too small for us to look at. So this is just recurrences, and that was what we found from the IPD.
Zachary Klaassen: And I think your point, BCG still works really well. It's working better now in the right setting, two years of maintenance at the minimum. I think you guys laid that out perfectly. We started off by talking, we can't throw everybody into these buckets for BCG plus IO. There's clearly patients that may benefit. Is there a couple of scenarios where you'd say if these get approved, you would say, I think we should really consider BCG plus IO.
Ashish Kamat: Yeah, no, absolutely. I think the term shared decision-making gets thrown around quite a bit, but this is exactly one place where you need to have that in there. Because first off, if a patient comes and says, "Hey, what is the best treatment right now for my non-muscle invasive high-grade bladder cancer?" I have to ask the patient, "What do you mean by best? Do you mean that you want absolutely lowest chance of recurrence or are you worried more about progression? What are you really worried about?" And some patients may say, "Hey, throw the kitchen sink at me. I don't care about side effects. I just want the best chance to not have a recurrence." In that case, yes, BCG plus IO clearly has benefit over BCG alone. But for the most part, you and I, when we talk to patients, we want to help them understand what works for them the best. I mean, what will help them with lower progression risk, what will help them with actually things that matter? And from that perspective, I think that we have to focus on the very, very high-risk group of patients. The patients with multifocal T1 disease, maybe T1B disease, T1 with multifocal CIS, the very high-risk categories that essentially you and I would normally be telling the patient, "You know what? You should consider radical cystectomy." And the patient says, "No, I want to try something." And you're like, "Fair enough. Why don't you consider BCG plus IO because you have a higher risk of having micrometastatic disease than the average person we're doing BCG with."
Again, the trials did not have enough event-free survival events in these categories, but there were some subgroup analyses presented at EMAC last year that showed that there is a hint of continued benefit or persistent benefit in that subgroup of patients. So this is in some ways a little bit of a data-free zone, but I think just having done this for a while, it makes sense, right? Take that highest risk patient and say, "This is something that I would recommend to you." The other group of patients is in patients who just can't tolerate BCG, they can only get an induction and maybe a little bit of maintenance therapy. In those patients, yes, we have other options. We have gemcitabine docetaxel, we potentially have other agents coming in, but today we can tell them, "You know what? Maintenance is important with BCG, but if you can't get maintenance, then at least adding IO to induction BCG will get you close to where BCG is with induction and maintenance alone." So it still doesn't beat BCG, but at least you get close to BCG. So that's one place to look at it, but I think we have to resist a temptation to use that as a crutch because folks that don't do this all the time, I'll hear them oftentimes say, "Hey, my patient can't tolerate two years of BCG. What are you talking about?" I think that's our shortcoming. It's not the patient shortcoming. Most patients should be able to get to at least two years, and it's our duty to make sure the patients get the appropriate treatment, which is BCG induction, and at least two to three years of maintenance therapy for the right patient.
Zachary Klaassen: That's a great point. And I just want to spin off real quick on that, Ashish. I think when I look at these patients, they get to 12 months, they get to 14 months. It's a lot of cheerleading and a lot of us pushing them to keep going because I think it's fatigue for visits and probably some bladder side effects. So maybe just talk about how you get that patient from that 14 months out to 24, maybe even 36.
Ashish Kamat: I think the first thing, Zach, is setting expectations. I tell the patient, "Hey, when you first start with BCG, you may not have side effects. Over time, the side effects are going to ramp up, and that's because your immune system is getting ramped up." So when the patient starts having side effects, he or she is actually happy about it. They're not thinking, "Oh my God, what's happening?" But at the same time, I don't want them to essentially be so brave that they suffer. And that's when I tell them, "Once you get to increase side effects, we will drop the dose." We've had EORTC 3R962 and other studies that have shown that it can safely drop the dose one-third. We've published where you can drop it at one-tenth, even 100th. So if a patient starts to get side effects, we will drop it for cause and it's duration that's more important than dose. Of course, we have antispasmodics and other things we can use. And I often in patients who really have severe side effects, will actually give them a prescription for Quinolone. Take six to eight hours after they've voided the BCG because there've been two or three Italian studies that have clearly shown that that does increase compliance with BCG installation. So like you said, well said, it's cheerleading. The nurses are involved, our PAs are involved, we are involved, and the patient's family has to get involved as well.
Zachary Klaassen: Yeah, absolutely. Well said. Great conversation, Ashish. Anything we haven't hit on you want to talk about? Any concluding statements for our listeners?
Ashish Kamat: Oh gosh, do you have two hours? No.
Zachary Klaassen: Sure.
Ashish Kamat: No, I think concluding statement is really in today's day and age, 2026, just because BCG is something that has been around for a long time, we shouldn't discard it. Just because it's old doesn't mean it can't be the best. I'll hear a physician say that, "Oh, it's been around forever. Let's move on." That's not the right thing. If you got the best thing in your armamentarium, just because it's old, don't discard it, learn how to use it the best you can.
Zachary Klaassen: Yeah, well said. Ashish, thanks so much for joining us. Congrats on the great piece in JCO.
Ashish Kamat: My pleasure.