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Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, a Professor of Urology and cancer research at MD Anderson Cancer Center in Houston, Texas. And it's again a distinct pleasure to welcome Dr. Eugene Pietzak from Memorial Sloan Kettering in New York. Eugene is an assistant attending surgeon and assistant professor at the Weill Cornell School of Medicine, and he is going to present to us, in this segment, his data on the trial of combination BCG and gemcitabine in patients with BCG relapsing non-muscle invasive bladder cancer. Eugene, if you're ready, you have the stage.

Eugene Pietzak: Thank you very much, and thank you for the opportunity to highlight this investigator-initiated trial. It is greatly appreciated. So here are my disclosures. None of them are relevant for this presentation, although some of this research funding does support this clinical trial. So, no need to tell Dr. Kamat this, or others, but BCG unresponsive disease has been recently well-defined to lead for registration type approaches for non-muscle invasive bladder cancer based on some guidance over the last five-plus years or so. And the definition of BCG unresponsive disease has been well described. And one of the caveats to it is patients need a particular amount of BCG, so-called an adequate amount of BCG, which is either two induction courses or induction plus maintenance, and then a recurrence within a certain timeframe.

And so the issue with this or potential issue for this is we are currently in an ongoing and persistent BCG shortage, and many patients have not received adequate BCG as a result of this. And this shortage, unfortunately, will be continuing into the near future, at least into 2025. So joint statements from the AUA, as well as the SUO and BCAN, do support the idea that if you are short of BCG, that it should be prioritized for patients for induction BCG rather than maintenance therapy. So some patients aren't receiving that. And then there may be other reasons patients may not be receiving maintenance BCG or so-called adequate BCG. And we know even for patients that are receiving adequate BCG, that late recurrences do still occur. So for patients that have recurrent non-muscle-invasive bladder cancer but do not meet the definition for BCG unresponsive disease, the standard of care for those patients, which I often term as BCG relapsing, but responsive non-muscle invasive disease, to signify that these are patients that you would typically rechallenge or retreat with BCG is the standard of care based off both the AUA guidelines, as well as European urology guidelines.

The expected outcome for the second course of BCG has quite a range to it, and that depends on the sort of the risk group or the clinical characteristics and pathological characteristics of the patients included in those cohorts. But it could range from anyone for about 25% to 67% of patients who do not respond to an initial induction course will respond to the second course of BCG. So the approach, at least in this clinical trial, is rather than trying the same six weeks of an induction course again and hoping for better results, perhaps there is a more rational approach that we could take for a combination to BCG. So when we looked at various mechanisms of resistance to BCG, what has been shown by numerous groups at this point is that the pre-treatment tumor microenvironment is quite predictive of BCG response. So the tumor microenvironment is enriched with effector T-cells. Those patients generally do better with BCG and have more durable responses. But if the pre-treatment tumor microenvironment is enriched with immunosuppressor cells, such as T regulatory cells, myeloid-derived suppressor cells, or tumor-associated macrophages, those are associated with an early risk of recurrence with BCG.

So this trial that I'm about to talk about was very much influenced by this very elegant paper from a group in France that basically demonstrated with each subsequent dose of BCG in the induction course, although there was a rise in the T-cells as well as the neutrophils with each subsequent dose, with BCG recruiting the immune cells like we know that it does, there is a concomitant rise within myeloid-derived suppressor cells as well that paralleled that. So what this group demonstrated is basically the ratio before BCG is given is pre-established. And if you have a high ratio of T-cells to myeloid-derived suppressor cells, those patients do very well in terms of both recurrence-free survival, as well as progression-free survival. However, if there are low T-cells and high myeloid-derived suppressor cells, those patients are at risk for early recurrence, and they show this balance between the two which is pre-established even before BCG is given.

And this is quite interesting for numerous reasons, giving bacteria into the bladder itself, although it is non-specific and recruiting immune cells, it is recruiting also these immunosuppressor cells as well. So when we looked at approaches to potentially targeting myeloid-derived suppressor cells and Tregs, what became almost immediately apparent to us is that one of the mechanisms, or one of the approaches potentially is gemcitabine. And this is of course because there have been several trials testing, intravesical gemcitabine both as a monotherapy, as well as in combination with docetaxel, demonstrating at least some early efficacy, although not durable responses. So this is an MSK-led phase II trial, and this is the SWOG trial phase II as well. Both showed an initial response rate of about 50%. But again, these were not durable responses. But if we look at comparisons, randomized controlled trials comparing BCG versus gemcitabine, we see in the BCG naive space, that BCG is clearly superior in terms of recurrence-free survival, but as patients get more and more exposure to BCG, gemcitabine then appears to become more efficacious than continuing BCG.

So the question is whether or not somewhere in between a combination of BCG and gemcitabine may potentially be beneficial. And so there are multiple potential mechanisms for synergy. Besides the immune-enhancing effects of gemcitabine, we know that gemcitabine also has direct anti-tumor effects as well within bladder cancer, as it is a standard treatment for both low grade non-muscle invasive disease, high-grade non-muscle invasive disease after BCG, muscle-invasive disease, metastatic urothelial cancer, and we know it has various mechanisms of action that may provoke an immunogenic cell death that could potentially release tumor neoantigens, as well as potentially inhibiting the repair of some of the BCG induced oxidative DNA damage as well. So potential areas for synergy.

There is also some preclinical data from mouse models of bladder cancer, suggesting that the combination of BCG and gemcitabine may be more effective than either one of these agents alone. Looking at prior trials that have combined chemotherapy and BCG, it generally favors that the combination is more efficacious than BCG alone, but these are focused primarily just on mitomycin and epirubicin. And even though these are more effective in terms of controlling or reducing the risk of recurrence, as demonstrated by this trial here, the reason why the combination has not really taken off, is because the combination of mitomycin plus BCG leads to substantially higher toxicity within the bladder itself, as demonstrated here. Even with dose reduction to 10 milligrams of mitomycin, there is still a substantially higher rate of grade three, grade four, bladder toxicities compared to BCG alone.

So when comparing, when looking at comparisons between gemcitabine and mitomycin in this randomized trial in patients who have already received prior BCG, we see that gemcitabine actually appears to be more efficacious than mitomycin, and it certainly seems to be better tolerated with almost half the amount of adverse events compared to mitomycin, and in subsequent meta-analyses comparing gemcitabine to mitomycin it is again demonstrated that gemcitabine appears to be more effective than mitomycin in terms of disease control, and it has less toxicity, and fewer side effects as well. And not to mention the fact that the costs are substantially lower for gemcitabine than mitomycin, making this combination of greater interest.

Looking at moving beyond just randomized trials of mitomycin and gemcitabine, including single-arm trials of the combination over here, mitomycin plus BCG has been assessed in over 1,200 patients across 18 trials. But looking at the combination of gemcitabine plus BCG, we were able to find a single prospective non-randomized trial that basically gave perioperative gemcitabine plus an additional dose before giving the standard induction doses of BCG. And although they found a statistically significant increase in improved recurrence-free survival at certain time points between the two, and showed that it was very well tolerated, this study alone is insufficient to draw any meaningful conclusions for this combination. So when looking at ways to potentially combine BCG with gemcitabine, what we wanted to be cognizant of is the fact that there was, at this point, some emerging data that suggest that bacteria may affect some of the metabolism of gemcitabine itself. And this is some of the early work looking at the microbiome.

So this to us at least suggested that instead of doing an approach like gemcitabine and docetaxel, where they are given in the same session, the same day, that there needed to be some separation between the BCG and the gemcitabine, even though it is obviously more convenient to give everything on the same day. So looking at the literature of the combination approaches with mitomycin and BCG, what became very interesting is there is the Di Stasi protocol basically that showed an improvement for this combination of BCG and electromotive mitomycin in terms of improving recurrence-free survival, progression-free survival, and actually bladder cancer and overall survival as well.

So the clinical trial we designed is basically based on this protocol here or the sequence of protocols here. And so the way that we set it up is very similar with two doses of BCG, a total of six doses with interspaced gemcitabine. So we went with the twice-weekly dosage of gemcitabine as used in phase I, phase II trial that was described here out of MSK. We wanted to start with gemcitabine in order to modulate the tumor microenvironment before BCG was given. Important to note is also that these patients will be receiving a total of six installations of BCG with maintenance. So, unfortunately, if patients do have recurrences after participating in this trial, they still are potentially eligible for BCG unresponsive trials. So potential opportunity to receive something that may be better or more effective than the current standard of care, but not losing an opportunity to participate in further clinical trials.

So with the inclusion and exclusion criteria, we tried to be very relaxed and were intentionally inclusive to try to enroll every patient for whom we would typically treat with BCG or BCG interferon. So we do have several patients who recurred after just a standard induction course, but we have multiple patients who have received additional BCG, whether it's two induction courses or some maintenance therapy, and they just did not meet the criteria for BCG unresponsive disease. So basically anyone that has recurred with a high-grade non-muscle invasive tumor, within 24 months of their last exposure that do not meet the FDA criteria for BCG unresponsive disease. And otherwise, the criteria are very similar to most other intravesical treatments, intravesical clinical trials.

We do have embedded correlatives in this that we are pretty excited and interested in. So besides looking at the molecular predictors of response and resistance to this combination, a major translational aim of this is we are hoping to demonstrate through a longitudinal collection of urine, as well as blood, that the addition of gemcitabine to BCG will reduce the number of myeloid-derived suppressor cells and T-regulatory cells that traffic into the tumor microenvironment. So going back to that French paper that I was discussing, we are hoping as we see either a flat curve over here for myeloid-derived suppressor cells, or even potentially a reduction in those cell populations as well over time from the addition of the gemcitabine.

So the phase I portion because we were concerned about potential toxicity between the combination based on what was seen for mitomycin with BCG, we went with a continual reassessment method, which is a Bayesian type of approach rather than the standard three plus three, which is often used in non-muscle-invasive bladder cancer trials, phase I clinical trials. So it's a little bit more prolonged than a standard three plus three, so it is a total of 25 patients to truly find the maximum tolerated dose. We kept with fixed doses of BCG, because we wanted patients to receive the most effective therapy, and we went with dose escalation of the gemcitabine, consistent with what was done in the phase one gemcitabine monotherapy trial here at MSK.

For the phase II portion, it's a Simon Two-Stage design, and our primary outcome is looking at the six-month objective response rate. So we are including both papillary only, as well as CIS, so although to date, most patients have carcinoma in situ component, and then we are setting our bar, we are looking for greater than 75% response rates compared to historically what would be thought about 55% or lower for the second course of BCG. So we are going to continue to accrue patients till we get to 43 total patients to determine the response rate, and the progress we have on the trial so far is we have 15 patients who have been enrolled to date at this point. The dose-escalation portion is complete now. There were no dose-limiting toxicities, which was excellent. The combination was very well tolerated thus far. So all patients that are now being enrolled, are being treated at the maximally tolerated dose of full-dose BCG plus 2000 milligrams of gemcitabine. And all these patients are also now being included in the phase II portion of the trial until we reach our goal of 43 evaluable patients.

And this trial will now be opening at Hartford Hospital later this month. So we are all very excited about this, and at least the preliminary very early data is very promising, but this trial is just really starting, and there is much to be done at this point, but it is looking very promising and is certainly a very well tolerated combination, at least to date. I do want to highlight, we are not the only group that is actually testing this hypothesis. There is now a cooperative group trial through the Alliance for Clinical Trials and Oncology led by Dr. Michael Woods. And this is testing the combination of intravesical gemcitabine plus pembrolizumab in patients with BCG unresponsive disease. So the excitement amongst us for intravesical gemcitabine as an immune-modulating agent, we should certainly have some data on this within the next year or two.

So I just want to thank both my partners in the bladder group here at MSK, as well as the urology service, and my mentors, both in GU medical oncology and pathology, and of course, thank you to the patients and the families that are participating in this trial and certainly to the funders as well that are funding this investigator-initiated trial. And thank you to Dr. Kamat and UroToday for highlighting our trial.

Ashish Kamat: Thank you, Eugene. This trial joins the whole armamentarium of trials that are exploding in this space, much needed for our patients, obviously, because BCG, as you alluded to, there is a shortage, and BCG, even though it works really well, it doesn't work in everybody and we need such mechanistically driven combination studies to move forward. So I want to, again, compliment you and your group with having a well-thought-out mechanistic study and designing it in such a way... Again, you recognize that it might be hard for patients to come for eight weeks, but you, again, fashion it in such a way that they could actually do it, and clearly, if they can save the bladder it's worthwhile. I just want to highlight a couple of points or actually ask you a couple of questions to highlight a couple of points. The actual logistics of the gemcitabine installation. Is there anything different in the way you are doing it in this study as opposed to the standard way we do gemcitabine in our patients?

Eugene Pietzak: No, it's given... We tried to replicate as much as possible for the standard of care. So it is given the way that we typically give it at MSK is twice a week, rather than the SWOG phase II trial, which was just once a week. So that is the only difference. So patients typically come in about two to three days after their initial dose of gemcitabine, so there is a little bit of separation of the two doses, but it is generally very well tolerated.

Ashish Kamat: And the question about the BCG, essentially you are using full dose on this trial. Have you seen in any of your, I guess, preliminary studies or preclinical work, whether a reduced dose BCG would also have similar effects on the myeloid suppressor cells and in other pathways related to the gemcitabine combination?

Eugene Pietzak: So we are using full strength and we've used it the entire time. For logistical reasons, we typically, even when we have a BCG shortage, we've been giving full strength, just because it's often hard to coordinate when you go to one-third dosing with patients and we didn't want to waste the BCG. So we have not looked at it and I have not come across any data looking at full strength versus reduced dose BCG in terms of its effects on the immune system.

Ashish Kamat: Okay. And then lastly, just in the interest of time, the last question for you is that you obviously alluded to the other studies going on with gem and pembro and others. In some ways, the de facto standard go-to regimen in patients who have not had a good response to BCG is now evolving to become gemcitabine and docetaxel, in the US at least, and based on several centers, studies, and then multicenter collaborative efforts. Have you considered using combination chemotherapy along with BCG? Obviously not in this phase, but any thoughts about expanding in that way?

Eugene Pietzak: Yeah, I think that's a great question. I think that is definitely an avenue of interest, I think, as you know, the data for gem, doce, although it is retrospective, obviously, it looks very promising and I think we do need prospective assessments of the combination. It is hard to know at this point in time whether or not combination chemotherapy is needed at this point. I think what we will do is we will see our results with gemcitabine monotherapy and then assess whether or not to further combination. There is some data that suggests that docetaxel may also have a similar effect on reducing some of the immune suppressor cells, but that data is far less robust with gemcitabine. I think in various different cancer types, gemcitabine in different models of cancer has demonstrated that where docetaxel hasn't necessarily shown that as robustly. But definitely an area of interest, I think, broadly across the bladder cancer community.

Ashish Kamat: So once again, Eugene, thank you so much for taking the time. In the interest of time, I'm going to wrap this up, but I do want to leave you with a few seconds, perhaps 30 seconds or so with your closing thoughts that you want to share with the audience based on what you presented.

Eugene Pietzak: Thank you, and thank you for the opportunity to present. I'll just say that I think this is obviously a single-arm trial, so part of it will be difficult to interpret compared to say a randomized trial, and those trials are certainly ongoing in the BCG relapsing spaces you alluded to with KEYNOTE-676 and some other files that are ongoing, we will have a better idea, a better assessment. But at least what we're doing here is we set up our correlatives to hopefully inform that, and then the next steps, potentially, for a combination like this, if it does look promising, would be to do a randomized trial for BCG. Because, unlike BCG, unresponsive disease, we obviously have a very effective comparator in this disease space with BCG. But I think sometimes we have to walk before we could run, so I think if we are able to demonstrate efficacy in this single-arm trial, that would definitely guide us towards a larger phase III trial.

Ashish Kamat: Couldn't agree more. Once again, thank you, and stay well and stay safe.

Eugene Pietzak: Thank you. Thank you again.