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Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and work at Vanderbilt University Medical Center. And we have the honor and privilege of having really two superstars in urologic oncology. We have Sunil Patel and Max Kates from the Brady Urological Institute at Johns Hopkins University.

And they are going to actually present their work on using combination sequential chemotherapy—gemcitabine and docetaxel—in the treatment of BCG-naive non-muscle-invasive urothelial carcinoma. So Sunil and Max, thanks in advance for spending some time with us and for sharing your data that's been recently published. So we'll turn it over to you.

Sunil Patel: Thank you, Sam, for the kind introduction. So we're going to just present a little bit of our data, like you said, the phase II trial of using sequential gemcitabine and docetaxel in BCG-naive, high-risk non-muscle-invasive bladder cancer patients. So as many of us know, with the BCG shortages and a stagnant era of treatment options in the high-risk non-muscle-invasive bladder cancer, this concept was really kind of formed by Max Kates.

And I helped out with this study as well, really trying to see what we can do and provide different alternatives to BCG. I mean, BCG is a very effective drug, and it's been around for many years. However, there is a proportion of patients that don't respond to BCG. And we need to have another option to provide for patients—an alternative to cystectomy, which has associated morbidity and mortality.

So this was a prospective, single-arm, single-center phase II trial. The inclusion criteria were adults over the age of 18 using the AUA high-risk stratification. And we selected patients between August 2020 and August 2022. Exclusion criteria were any concurrent upper tract urothelial cell carcinoma or prior intravesical therapy and, again, BCG-naive. And they had to be enrolled within 90 days of their TURBT.

The intervention was an induction phase, which was weekly therapy for six weeks, followed by a cystoscopy at three months, and then monthly therapy for two years in responders at that three-month cystoscopy. And the analysis was—the primary endpoint was complete response rates at three months. And the secondary endpoints, excuse me, were 12-month high-grade CR rates, recurrence-free survival.

And then we wanted to look at the toxicities as well. As you can see, most of the patients were around 68 to 69 years old. Eighty-four percent of the patients were male sex, fitting the kind of standard population. We did see significantly higher numbers of Caucasians compared to African Americans. We did have almost a split of former and never smokers in this group.

And the interesting thing, which was really great about this study—even though we only had one CIS—but we did have a mixture of high-grade Ta's, high-grade T1s, with and without CIS, and a pure CIS as well. Because as we know, there are some mixed response rates with patients with CIS.

If you look at the swimmer's plot over here, we tracked all of our patients and were surprised and had very good outcomes. So at three months, all patients had a complete response rate. And at 12 months, 92% of patients had a complete response rate. No patients were upstaged to T2, underwent a cystectomy, or developed any clinical, nodal, or metastatic lesions. The safety profile of this drug combination: about 20% of patients had grade 3s. No grade 4 or 5s, and grade 1s and 2s were very common, very similar to the BCG profiling.

And over 80% of the patients did complete their induction without significant side effects preventing them from completing it. If you look at the patients on the swimmer's plot, there were a few that actually had a positive—or one that had a positive cytology, underwent a complete, thorough workup, and was deemed negative. If you look at the Kaplan-Meier curve over here on the right, you see our recurrence-free survival rates at the 12 months—again, 92%.

So again, very promising in the BCG-naive space. Again, a smaller study, only 25 patients; however, very promising results with a mixture of CIS patients, high-grade T1s, and high grades with CIS as well. With that, I get to open up to any questions.

Sam Chang: Sunil, that was fantastic. The work that Max has helped lead and you guys have done this in a prospective fashion, as opposed to a lot of previous publications that have extracted a few of the BCG-naive patients and looked at the results. You guys have done it prospectively and really looked at things. Tell me first—

And I'll turn to Max. Tell me first, how did you all decide this cohort? Was this basically—you had trouble accessing BCG—let's, basically, all eligible patients, we're going to start this? Or tell me a little bit about that initial selection process over the last couple of years.

Max Kates: Yeah, Sam. And thanks for giving us this platform to talk about this. So I think it was 2015 where we had the prior BCG shortage. And we had been using Gem/Doce there, thanks to Michael O'Donnell really kind of coming up with it at University of Iowa, and then my mentors at the time, Mark Schoenberg and Trinity Bivalacqua, adopting it.

And during that BCG shortage in 2015, we ran out completely of BCG. And we started using Gem/Doce. And then we got the BCG back, and we looked at our patients who had gotten Gem/Doce, and we were like, they did great. We should have done this in a prospective study during the shortage, and said, if this happens again, we're going to write a phase II protocol so we can do this kind of prospectively.

Because you're right. I think in the community, those of us that have been using Gem/Doce have been trying to proselytize it. But in medicine, we're evidence-based. And the level of evidence for a retrospective series is just not going to be up to the mark of a prospective phase II trial. What's the difference? You have a safety and monitoring board that's regularly evaluating our patients and looking at how we document toxicity.

We have a protocol where these patients have to be evaluated every three months. So there's just significant differences between a prospective study and a retrospective study that I would think was hampering Gem/Doce's time in the sun. And so based on that, we said, OK, if we get the sense that a BCG shortage is coming, we're going to start this program.

And we actually wrote it ahead of time, primed for a time when we thought that there was an ethical—meaning where we really could suggest that patients could go on to a single-arm Gem/Doce, BCG-naive study ethically. And so that's how this all came about is really this wave of the BCG shortage. We took advantage of it this time.

Sam Chang: Well, that's fantastic. Sunil, can you tell us a little bit about how you all logistically have set this up to try to increase the efficiency of this process? That's the complaint that I hear from those in practice—that just the logistics, the timing, et cetera, makes it more difficult to actually engage in this process. Tell us a little bit about how you all do that and get it started.

Sunil Patel: Yeah. So I think that's a great question. Kudos to Max Kates, because Max Kates did a lot of the legwork for this. But I think getting a phase II study like this off the ground does require a lot of buy-in. However, it requires frequent communication with your pharmacy team, with your nursing staff as well. And I know that you're familiar with this as well.

I mean, getting patients to the time slots, even just to do the sequential treatments. How are we going to handle the drugs? The waste of it, right? Because it's a chemotherapy drug. So there are those issues with that. And a lot of the successes that we've had with this trial and also the BRIDGE trial—that Max's large study right now—is the constant communication with nursing staff, the pharmacy, and trying to get that, making sure that we're all aware of what's going on and see how we can help each other out.

And the logistical aspect of that does take time, and it does take patience and does take more communication than sometimes we think that we're going to have to do. But I think if you take a step back and understand that there are limitations from every group—some pharmacy creating the drugs or sending the drugs, the nursing team and their ability to do that—I think if you can understand that and work with your team, and work with your providers as well and your partners, I think it really is a recipe for success.

Max Kates: Can I just add one or two—

Sunil Patel: Yeah, please.

Max Kates: —just tips. So chair time, when you compare BCG to Gem/Doce, is about 30 minutes longer with Gem/Doce. So we don't keep the chemo in. We put one drug in, it washes out, the other drug goes in, and then the catheter is removed, and then they go home. So that decreases our chair time. That's first. Secondly, chemo can be given in clinic.

So some centers mandate that chemo is given in an infusion center similar to medical oncology. We firmly believe that should not occur because our urology nurses are much more adept at catheterizations than an infusion nurse. And so we fought for that. And then BCG requires a hood to prepare, and it's a complex drug to prepare.

Actually, the chemos we use are prepared every day in our hospital much more widely. And so there's—from the pharmacy side, it's actually more straightforward for them to mix our chemo drugs than BCG. So I think that this whole thing about Gem/Doce being more complex has some truth to it in terms of chair time. I mean, that can't be argued. But there's other aspects that I think are more straightforward.

Sam Chang: Now, I think those are excellent points. And the only thing that I would add is that we obviously depend on our co-partners, our nurse practitioners, and our PAs who really helped and have helped integrate this whole process into the treatment of these patients. Clearly, at least anecdotally, we have similarly had actually very good success with this combination, good tolerance.

The efficacy profile—we really think there's a true signal there. And I agree totally with both Dr. Kates and Dr. Patel regarding the importance of evidence. But, of course, I'm going to push a little bit and go beyond evidence to try to figure out what you all do. All right.

First is a hypothetical question. Why do you think the combination of these two medicines is that perhaps—so far, it seems, at least signal-wise—much more effective than each of these agents individually? So I want to start with that hypothetical question to either one of you.

Max Kates: Yeah. So the way I'll answer that question is saying, when I was a resident, I worked in the lab with Trinity Bivalacqua, and we developed a rat model of bladder cancer. And then I spent about six months giving intravesical instillations of various agents to the rats. And then we would dissect out the bladders and—

Sam Chang: Small catheters.

Max Kates: Small—very small angiocaths. Exactly. It was not with—the syringe was crazy. It was a $100 syringe, a glass syringe. And across the board, the single agents did worse than combination agents, regardless of what the combination was, which is fascinating. So what did I take from that? I always think one of my earliest mentors, who was Jim McKiernan.

And he once wrote me an email with just the phrase "medical oncologists figured out 40 years ago that multi-agent chemotherapy was better than single agent. Why have urologists not figured that out yet?" And that always stuck with me as like, yeah, we figured this out in the field of medicine, but urologists have been stuck on monotherapies.

So I'm not really answering your question. Maybe Sunil can come up with a more scientific answer. But from the lab and just from what we know, combination therapy should be better than monotherapy, probably from different mechanisms of action. But I never figured out the mechanism.

Sunil Patel: Yeah. And I think, Max—I'm piggybacking off of Max's comment. I think he's completely right in that mentality. And I believe it was one of a GU ASCO meeting. Very similar concept was presented in that sequential or the combination chemotherapy drug. And just like systemic therapies where you have, even for a neoadjuvant chemotherapy, you have gem/cis or MVAC, just the mechanism of action, I believe—I think we can translate that into the bladder as well.

And potentially causing certain tumors—or certain cells may be responsive to one or the other and then release some of their antigens, and then help, obviously, I think, that whole combination of—or that thought process. Intravesical chemotherapy also may be a form of immunotherapy by releasing these antigens and APCs help with that process.

But I do believe that when you hit the patient with two different medications, you're covering more ground, so to speak, and allowing for the drug to work better on multiple cells. Because we know cancer—as we know, not all cells are the same. And I think that giving sequential gemcitabine and docetaxel has that same—or we can hypothesize that's the reason why.

Sam Chang: Yeah. I think that those are important rationales. And clearly, Dr. McKiernan has done triplet therapies and combinations. And the nice thing that I like with this doublet, if we can call it a doublet, I guess, is the fact that, at least from what I can tell from what we've read from our own experience, the side effect profile, the tolerability profile is really not significantly negatively impacted by this doublet.

There is the increased chair time, just as Dr. Kates said. But in terms of overall tolerance, I don't think there's been a big change. Last question, and this is one that is borne out on the success of this treatment. We have done our six-week induction course. We're on our monthly maintenance course. So question number one, after a year or two of monthly maintenance, patients are disease-free.

Obviously, this is not necessarily evidence-driven at this point because we're early on in gathering this data. What do you all do at that point? Do you stop it totally? Do you go to every three months? Do you go to every six months? Tell me what you all do with those patients that have responded, that the side effect profile continues to be favorable. What do you all do?

Sunil Patel: I believe I'm speaking for—hopefully, I'm not overstepping—but I'm speaking for both Max and me, that we usually stop the drug altogether at that point and just follow them with routine cystoscopies and cytology every one to two years with cross-sectional imaging. I do believe—and this is my own opinion, again, not evidence-based.

I do believe that if we've hit a CR and the patients are doing fine after two to three years, like BCG too, the more drugs that we give in the bladder, we may then potentially add more morbidity and cripple the bladder, so to speak. And I think if we've hit that two-year kind of CR rate, I think we're at that sweet spot where we stop all medication, let the bladder calm down.

Because sometimes there is a tipping point. And I'm sure that we've all seen that with our patients, that their bladder now turns—even though they're NED, we've crippled their bladder. And so I think there is the sweet spot. But we routinely do not give any more drugs after that.

Sam Chang: All right. I said that was the last question. But I get dealer's choice here. OK, really the last question—you've done six-week—real-world situation, six-week induction. You reevaluate the bladder in any way that you reevaluate—anesthetic in the office, whatever. And if things look better, there's less disease. You all had 100% CR rate at that three-month mark and initial evaluation.

What if you don't? To be honest, we've done a repeat induction course of the combination. No specific data, but if you all face that situation, what would you all do? Clinical trials are going to take off the table. You may or may not have BCG. You all haven't been put in that situation. Honestly, we have. So I was wondering what you all would do.

Max Kates: Yeah. I mean, we have been put in that situation, just not on this particular study.

Sam Chang: Sure.

Max Kates: So I think, in the first three months, if there's a high-grade Ta or a CIS recurrence similar to BCG, I advocate for a full six-week re-induction. We built that into the BRIDGE trial. So re-inductions in those situations are allowed. So that'll be nice because we'll see how many are in that situation on study, and maybe we'll have some signal of—

Sam Chang: Absolutely.

Max Kates: Correct. Because you're right, we don't know. And I think to myself, OK, well, if we don't have BCG, then we're left with some recently approved agents. Certainly left with cystectomy, which, I think, may be overkill for like a small Ta recurrence at that three months. And so the question is, is a re-induction of Gem/Doce going to be in the patient's better interest than one of the newer agents that's been FDA approved?

And I would argue, yes, because it keeps the newer agents in our back pocket. And it probably will work as good, if not better, than those agents. In my heart of hearts, I believe so. Most of the time, we'll do a re-induction if it's small and not some obvious progression on therapy.

Sam Chang: Yeah. I agree. And I think the safety-first approach that you advocate regarding, to me, a big difference between the T1 versus Ta, and even CIS, I'm really pushing that category of patients to—let's try to preserve the bladder. Let's think about options. T1 disease still, as I told patients yesterday, and I'm sure I'll tell them today, really significantly worry me. And so I agree totally with your thought processes.

So we could talk about this for a long, long time. I very much appreciate, number one, all of your scientific efforts. The BRIDGE trial that Dr. Kates is leading, obviously, is going to be hugely impactful and will give us so much information down the line. So we look forward to those results. And thanks to both of you all. And we look forward to spending some more time together on UroToday and learning from both of you experts. So thanks again.

Sunil Patel: Thank you.

Max Kates: Thanks so much, Sam. This was fun.