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Sam Chang: Hi. My name is Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee. And we have a real honor of being joined today by Dr. Gal Wald as well as Dr. Gene Pietzak.

Dr. Wald is actually a resident at the Weill Cornell University Medical School, and he is doing research at MSKCC with Dr. Pietzak focusing on bladder cancer. He's going to be presenting a late-breaking abstract that was accepted at the SUO 2024 meeting, looking at actually intravesical therapy combinations for BCG-unresponsive disease. So I'll let Dr. Wald actually go ahead and give his presentation, and we'll then ask him, as well as Dr. Pietzak, some questions.

Gal Wald: Awesome. Thank you so much for the invitation. It's a privilege to be presenting to you today. Before I delve into the preliminary results of our phase II trial, I do want to provide a brief background and rationale for a multicenter phase II trial of intravesical gemcitabine and BCG for BCG-exposed non-muscle-invasive bladder cancer.

So BCG-exposed patients represent a large cohort of non-muscle-invasive bladder cancer patients. We know that recurrences after BCG monotherapy are common, and these patients are typically re-challenged with an additional course of BCG. However, they tend to have poor response rates. So combination strategies have been recently developed to enhance the effectiveness of BCG to prevent BCG-unresponsive disease and progression.

The current landscape of BCG-based combinations includes options such as addition of immune checkpoint blockade or the IL-15 superagonist or intravesical gene therapy. However, some of these medications have an unacceptable toxicity profile for the majority of non-muscle-invasive patients. Some only have single-agent activity, and some are very expensive, costing more than half a million per year per patient.

Intravesical chemoimmunotherapy represents a whole other treatment paradigm. It’s been found to be more efficacious than BCG alone, yet many of these studies only use mitomycin, which is a known vesicant with urinary side effects.

When evaluating the efficacy and safety of specific chemotherapy agents, intravesical gemcitabine compared to mitomycin specifically is more effective, it’s better tolerated, and is less cost prohibitive. Its mechanism of action has direct cytotoxicity in bladder cancer, but it also enhances the immune system via immunogenic cell death. It depletes immunosuppressive cellular populations such as regulatory T cells and MDSCs and enhances cross-priming.

We found that in preclinical orthotopic mouse models, the addition of gemcitabine to BCG is more effective than either agent alone, which suggests an additive or possibly a synergistic effect. Based off this data, we designed our BCG phase I trial, where we found no dose-limiting toxicities. The majority of patients were treated at the maximum tolerated dose of 2,000 milligrams of gemcitabine, and the treatment was well tolerated with no patient experiencing grade 3 to 5 events.

In light of these findings, I want to turn our attention to our phase II trial of intravesical chemoimmunotherapy with gemcitabine and BCG. We hypothesized that this combination will have improved response rates compared to historic outcomes with retreatment with BCG alone. Our primary endpoint was a complete response at six months, and we used an optimal Simon two-stage design, where a complete response of 55% was selected as the null hypothesis, with a CR rate of 75% to move forward with the study.

Patients were eligible for the trial if diagnosed with high-grade non-muscle-invasive bladder cancer, and were exposed to BCG within 24 months. Exclusion criteria consisted of those with BCG-unresponsive disease, contraindication to BCG, evidence of concurrent extravesical urothelial cancer, or history of muscle-invasive or metastatic disease. We show our 10-week therapy timeline in the bottom right corner of the slide.

Patients receive gemcitabine twice weekly in weeks 1, 4, 7, and 10, and BCG weekly in weeks 2, 3, 5, 6, 8, 9, followed by one year of maintenance BCG. Consistent with other non-muscle-invasive trials, the majority of patients were elderly white men who were former smokers. The median number of months since prior BCG instillation was six months. Twelve percent of patients received prior maintenance BCG, and 12% received at least two prior induction courses of BCG.

Histology of the trial entry is shown in the bottom-left table. Approximately three-quarters of patients had CIS with or without papillary disease. The majority of patients had noninvasive bladder cancer. For preliminary efficacy results, 94% of patients had a complete response at six months. At 12 months, our CR rate was 81%. We show a swimmer plot on the right, demonstrating the time to high-grade recurrence, as well as events beyond the trial period.

When evaluating the CIS cohort, 97% of patients had a complete response at six months, which mirrors the results of the overall trial population. We next demonstrate a recurrence-free Kaplan-Meier survival curve that calculated high-grade recurrence-free survival. At 12 months, it was 85%. And at 12 months, cystectomy-free survival was 100%.

The majority of patients experienced a grade 1 treatment-related adverse event, as expected with intravesical BCG or chemotherapy, and also consistent with our phase I trial. Only two patients experienced a grade 3 adverse event: a urinary tract infection requiring a single dose of IV antibiotic in an outside ER, as well as pneumonitis attributed to BCG that resolved, fortunately, in a long-term responder. Notably, no grade 4 or 5 toxicities were observed.

In conclusion, GemBCG in BCG-exposed non-muscle-invasive bladder cancer demonstrated excellent early oncological efficacy with a favorable toxicity profile. The phase II trial is fully accrued. Data is maturing, but we also have ongoing correlative studies.

We found evidence that the addition of gemcitabine favorably augments the tumor microenvironment based on changes in urinary cytokines and chemokines profiles, but additional tumor and urinary correlatives are ongoing. And the GAIN Trial is now set to open in May 2025. This is a phase III randomized trial comparing gemcitabine BCG versus BCG alone for patients with BCG-exposed high-grade non-muscle-invasive bladder cancer. And we’re very excited to have that started. Thank you.

Sam Chang: Dr. Wald, thanks so much for giving that presentation, the late-breaking abstract from the SUO 2024 meeting. I have maybe 1,000 questions to ask, but I'll keep it limited because the study invokes a lot of thoughts and a lot of observations. And I'll go straight to the hypotheticals and what we do.

First, I'll ask either Dr. Wald or Dr. Pietzak—how did you all come up with that treatment schedule? It's a pretty intense 10- to 12-week schedule, but then it looks like no maintenance afterwards. So how do you all come up with the alternating schema?

Eugene Pietzak: I think I could take that, Sam. Thank you. The regimen’s largely based off the Stasi protocol that was published in Lancet Oncology in 2006 or so, and that was using electromotive mitomycin as well as BCG in sort of that sequential pattern. So we modeled it after that in large part because, to my knowledge at least, that’s the only clinical trial that’s ever shown a combination or any treatment that’s superior to BCG—

Gal Wald: BCG alone.

Eugene Pietzak: —with respect to recurrence-free survival, progression-free survival, and bladder cancer–specific survival. But as you know, it’s never used, in part because of the difficulty with the device, but also some of the side effects from electromotive mitomycin. Now, the Australian group recently completed a phase III randomized trial. It hasn’t been reported out, but it’s using passive aqueous mitomycin in combination with BCG. Those are nine-week regimens typically. So they go two weeks BCG, mitomycin, two weeks BCG, mitomycin, two weeks BCG, then mitomycin, I believe.

Ours—because we have this hypothesis, and Gal showed the correlative sort of supporting this—is that the addition of gemcitabine may have some immune-enhancing effects. We wanted to prime the tumor microenvironment. And the way that we typically give gemcitabine at MSK was based off the Guido Dalbagni phase I and phase II studies that Dr. Dalbagni and Dr. Bajorin ran in the early 2000s, and that’s twice-weekly gemcitabine.

Overall, the regimen is very well tolerated. But I do agree there is—it’s a lot more additional visits. So we were giving eight additional instillations with the gemcitabine in our phase I, phase II. And as we saw in the phase I and now the phase II, there wasn’t any added toxicity that was reported, and patients typically tolerated it. But it is terribly inconvenient, for sure.

And so when we were moving forward to the phase III through the NCI cooperative group, there are certainly compromises that sometimes need to be made. And so we’re reducing it to six instillations of gemcitabine. So six BCG and six gemcitabine. And it’s the middle dosing. So we kept biweekly in the first week and the last week because in our phase I, we actually saw no reported grade 1 or grade 2 toxicities really in week 1 or 10. Most of the side effects were actually from the BCG itself. So we kept those, and we compromised and cut out the middle. So that’s just once-weekly gemcitabine in the middle.

Sam Chang: Now, figuring out that rationale is obviously always a difficult one. I love the idea of having some cell kill initially with a cytotoxic chemotherapy to stimulate and then giving the BCG. It makes at least hypothetical sense quite a bit. Any thoughts, as this trial rolls out, the definition of BCG-exposed then would be any less than six treatments? Tell me the definition regarding that for enrollment in the trial.

Eugene Pietzak: So for the phase III, we tried to have—actually, for the phase I and phase II as well—we have pretty liberal definitions. So based on the phase I, phase II, there are some patients that by definition now meet BCG-unresponsive criteria. When I initially wrote it back in 2014, 2015—it’s been a while now—the definition had slightly changed to now allow for recurrence within 12 months with a CIS recurrence, as you know. So we have some of those patients included.

But we basically wanted to try to include everyone in this phase III who does not meet the current definition of BCG-unresponsive disease. And a reasonable urologist would consider retreatment with BCG for the patients. And so it’s pretty liberal. Patients could have prior intravesical therapies, whether that’s nadofaragene or BCG-IL-15 or prior gemcitabine. We’re basically allowing all of that. It’s just high-grade recurrence within two years of last BCG exposure and does not meet the definition of BCG-unresponsive disease.

And so it’s pretty liberal. And I think the only thing in terms of amount of prior BCG, we kind of just want—the key to this, because it is far more intensive type of regimen in terms of the visits and the intravesical treatments, we wanted to make sure we’re getting patients who previously tolerated intravesical therapy. So typically, if they did well with their BCG, flew through it without any problem, they do very well with this 10-week regimen. So all these patients typically will have to have at least five of six of an induction course, typically.

Sam Chang: Got it. No, that makes sense. And obviously, it’s a randomized trial versus BCG, and I’m assuming the BCG would be once a week for six weeks. Is that correct?

Eugene Pietzak: Yeah, it’s standard. And to the point, previously on the phase I, phase II, everyone got SWOG-style maintenance BCG for at least 12 months. A lot of it also depended on the BCG shortage. Unfortunately, we’re using commercial supply, so we were somewhat affected by that.

But for the maintenance regimen in the randomized phase III, it will be standard SWOG maintenance BCG for at least one year in the control arm, BCG alone. And then for the GemBCG study arm, what we’re going to do is have a priming dose with twice-weekly gemcitabine before once a week for three weeks of BCG. As Gal showed in the preliminary results so far, we’re seeing excellent results. But we are seeing some later recurrences at that 18, 24 months or so. So we’re seeing if we could further sort of boost the immune-enhancing effects of gemcitabine here.

Sam Chang: Crystal ball, OK? You’re thinking ahead. I’m smiling because you mentioned the initial gemcitabine trials with Dr. Dalbagni at Memorial. That was actually going on when I was a fellow there. I mean, some people would call that a century ago because it basically was.

But as you look ahead and you try to predict what happens, I’m going to ask Dr. Wald this first. This seems to make a lot of sense. Do you think this combination regimen first line might be better than BCG alone?

Gal Wald: Yeah, that’s an excellent question. I think we right now don’t have the answer to that. Making this treatment regimen first line, like Dr. Pietzak mentioned, does represent a form of treatment intensification with a 10-week course as opposed to a six-week course. But right now, we are focusing on the BCG-exposed space, which is fundamentally different than the BCG-naive or the BCG-unresponsive disease. I think once we have found or better understand the landscape of BCG-exposed disease, we could potentially move to a more naive state. But a lot more needs to be done. Our data has to mature, and our phase III trial has to demonstrate superiority as well.

Sam Chang: Yeah, I agree totally. As you, Dr. Wald, are finishing up your research year, tell me what your next steps are. As you go through your residency, what other trials are you interested in, or what other trials are you actually forming together perhaps with Dr. Pietzak?

Gal Wald: So I have six more months of my research year, and then I’ll be a clinical PGY5 in a six-year program. So I’ll be applying to the Society of Urologic Oncology fellowship. One of my other focuses of this year is actually understanding the role of surgery in the metastatic urothelial carcinoma state. We have seen some presentations at SUO demonstrating that after the FDA approval of enfortumab vedotin and pembrolizumab, patients have durable responses. However, some of those patients also have locally progressive disease. So one of my other projects during this year has been trying to better understand how we can possibly select patients for consolidative surgery in the metastatic state. And I think this is a very exciting time in the field of bladder cancer, and I’m very much looking forward to sharing my results in the future.

Sam Chang: Well, we look forward to hopefully having you share that with us here. And I just want to actually commend all the activities and the research. Obviously, to be chosen as one of the late-breaking abstracts from the SUO is really a testament to your work. But I also want to obviously give a shout-out to your mentor, Dr. Pietzak, who was the one who really advocated in terms of “this is exciting work” and went to the abstract. You did a wonderful job presenting it.

And thank you again for sharing some of this data with us and your expertise, and we’ll look forward to future research.

Gal Wald: Thank you so much.

Eugene Pietzak: Great. Thanks, Sam. And I just want to echo what Gal said. He is definitely applying for SUO fellowships next year, so he’s someone for everyone to keep an eye out for.

Sam Chang: Be on the lookout for him. All right. Great. Thanks, guys.

Eugene Pietzak: Great. Thanks, Sam.

Gal Wald: Have a good one.