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Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt University Medical Center. We're quite fortunate to have Dr. Mark Preston. Mark is actually an associate professor at the Brigham and Women's Dana-Farber conglomeration of institutions associated with Harvard Medical School. He really doesn't need an introduction. I could spend more time talking about his institutions, but more importantly, we're here to talk about what Mark has been looking at, which is a combination of chemotherapy agents for non-muscle invasive bladder cancer.

So, Dr. Preston, thank you for spending some time with us, and we look forward to going over perhaps the recent Urologic Oncology paper that you all put together, but then anything else you find interesting when it comes to the combination of chemotherapy agents.

Mark Preston: Great, thanks, Sam, very much for the opportunity to chat tonight. Also, I always enjoy talking about non-muscle invasive bladder cancer and various trials and treatment options. It's a space that didn't have a lot of options for years and now all of a sudden, there's an abundance of different trials and agents and companies, and interest from all levels, which I think is great for patients.

What our group was working on here was basically looking to build on and see if we could replicate Mike O'Donnell's great work out of Iowa. He pioneered this combination of gemcitabine and docetaxel years ago that they had published on, and we thought, "Well, we need another option." This was, what? About 2018 or so, I think, when we first started using it, it was something that was available. Older chemotherapies that were readily available, and we had the protocol that he kindly shared with us, and the thought was, "Okay, if we're going to institute this, we'll see if we can do it in a similar fashion."

And then what we were able to do years later was to actually look back with our first hundred or so patients between us and MGH across town, to see what results were. And this was just published in Urologic Oncology, and I think we can run through it and then discuss.

So as you can see, this was a group effort between us here at Brigham and Women's and the group over at Mass General. A lot of work by Kendrick Yim, who's one of our senior residents who's fantastic. He's actually applying for an SUO fellowship and he's been a real dynamo with this study and others.

And so, this was the recent publication here, looking at sequential, intravesical gemcitabine docetaxel in recurrent, high-risk non-muscle invasive bladder cancer following BCG therapy. So obviously, we know BCG is the standard of care, but it does have significant rates of recurrence and progression, and it's in that population. Those who've been exposed to BCG typically are unresponsive to BCG. And then we're looking at what treatment options are available. Historically, there wasn't a whole lot, and there was valrubicin approved decades ago that didn't have great efficacy and it hasn't been used widely. And then there were a number of, obviously, clinical trials more recently. IV pembrolizumab, which is FDA approved a few years back now, and more recently nadofaragene, which is available and was at our P&T committee meeting a few weeks ago. So, we hope to have that on board here soon as well, as an exciting option.

But prior to that, when we were in 2018 through the more recent years, in addition to putting patients on trials, we wanted something that we could use reliably and, based on Mike O'Donnell's work out of Iowa, which was fantastic, 50% high-grade recurrence-free survival at two years. Obviously, it was a multi-center study, but it was also retrospective but had real promising efficacy. So, we took that protocol and we looked to replicate it. He's been great to work with for years in sharing and troubleshooting and setting up a clinic flow that worked well.

And so, what we published on here was our own multi-institutional retrospective analysis of patients treated with induction intravesical gem/doce for recurrent high-risk non-muscle invasive bladder cancer after BCG therapy. Our cohort included 102 patients between ourselves and Mass General. Maintenance therapy, which we provided as per protocol, was given monthly, ideally up to two years for those without high-grade recurrence and surveillance cystoscopies. Our median follow-up was 18 months. The median age, as you can see in Table 1 on the side there, was about 72 years and the breakdown number of prior BCG induction courses, median number of prior BCG instillations was 12, and it was just a smattering of other treatments. BCG interferon when that was available and we were given that, some had mitomycin, some had even gemcitabine monotherapy. So, these are obviously some heavily pretreated patients on occasion.

And then this is the primary results here. So, what we looked at initially was recurrence-free survival overall. Kaplan-Meier here, but then also high-grade recurrence-free survival. And we found that the gem/doce combination provided a durable remission.

So, you're looking at high-grade recurrence-free survival at 12 months was 67% and then even extending it out to 24 months was 49%. And what was remarkable was that it was actually very, very similar to the numbers that Dr. O'Donnell and his group had reported on in that multi-institutional study, which was also approximately 50% at two years.

So, we thought similar protocol, obviously similar patients, but while not a randomized trial, it's always nice when you can validate these studies in your own population of patients that you're seeing on a day-to-day basis. It's not just stating someone else's retrospective study. This was our own data in our own center, giving this gemcitabine and docetaxel combination and having good results.

The other thing we broke down was to try and see if there was a way to predict which patients might respond better to the gemcitabine and docetaxel. Something simple was just looking at breaking down the BCG unresponsive disease into those that were BCG refractory versus BCG relapsing, and the BCG refractory disease seemed to have a worse response to gem/doce.

It was still 37% at two years, so it's still better than a lot of other things that were available. So, it's not like you wouldn't give it to these patients, but it is something that I think warrants further investigation as well to see if you can better predict patients who might respond to that versus going to an earlier cystectomy, for example.

When breaking down the clinical risk factors that predicted response, the one that jumped out again was this BCG refractory one as having a higher likelihood of not having success. In terms of tolerance, it was well tolerated. Anybody who's used this, it is well tolerated. There were some adverse events, the majority of which were the ones that you would expect with intravesical agents, like dysuria, occasional hematuria, some urgency frequency. Typically, it was bladder-related symptoms, not as much of the systemic fatigue and things that you would get with BCG, for example. There were only treatment side effects impacting the schedule in about 7% or so, which is quite low. So, most patients were able to get the treatment without issues, and we had a urinary tract infection rate of about 5%, which is pretty standard with most non-muscle invasive treatments.

The conclusion that we had from the paper is that it was very well tolerated, with a low rate of treatment schedule alterations, and then a durable response rate, 65% at 12 months, which is comparable or better than a number of the current trials of what we're seeing now of the newer agents coming out, and 49% at 24 months. There were some that progressed onto muscle invasive disease. We had about 20 patients undergo radical cystectomy at a median of 15 months from induction, and we did find that those with BCG refractory disease were more likely to have a high-grade recurrence versus relapsing. And trying to put this in context, one of our other residents, Thomas Wang, did a great job pulling together this letter looking at ongoing clinical trials, those that have FDA approval like pembrolizumab, nadofaragene, and looking at what their three and 12 months high-grade recurrence-free survival rates were.

And you can see gem-doce is certainly comparable if not better than some. Obviously, the weakness is this is a retrospective study, whereas these other ones were randomized trials with protocols and things, but it does... you need to compare it somehow, and this is a nice way of doing it.

You can see the initial guidelines where they thought you'd ideally want at least a 30% high-grade recurrence-free survival at 12 months. And we've had some approvals at less than that, like pembrolizumab, for example. But I think some of the newer ones are going to be hitting that target with less of a struggle.

In looking at other agents, you can see our recurrence-free survival rate at 76% at six months, 62% at 12 months, which is very, very similar to the publication from Dr. O'Donnell and then the rates at 12 months with the other agents as well.

In terms of future directions, ideally, you have a randomized trial of gemcitabine and docetaxel. I think the challenge is obviously that these are generic medications. There's no drug company that's supporting gemcitabine and docetaxel that would fund that, and it's very expensive to do a trial. I think efforts through funding agencies like the DOD or NIH are a valid way to go. If the medication is cheaply available, it is a trial that you can run fairly, I think, efficiently.

One of the other things that we're working on here is also trying to see if we can better predict who's going to respond to it or not. This is work now that Kendrick Yim is doing, actually trying to see if we can identify genetic alterations associated with response, using an extreme phenotype analysis. So, we've got whole genome sequencing that's underway now from the BCG refractory patients who either had a very durable response to the gemcitabine and docetaxel, or those who had progression or persistence despite the gemcitabine and docetaxel, to see if there is a sequencing pattern that might better predict who should get gemcitabine and docetaxel versus those who might be better off going right to either early cystectomy, or one of the other agents.

Sam Chang: Mark, that's fantastic. Yeah, as you think about these different treatments, I think the first thing we always say is you're never supposed to compare study to study, cross-study comparisons, but then again, every single one of us does it, and we all get some picture, some idea, although statistically not valid, just as you said, it warms your heart when you see that your results are very similar to Dr. O'Donnell's.

Secondly, what strikes me is of the currently available FDA-approved agents for BCG unresponsive, the valrubicin, which very, very few people use, pembrolizumab intravenous, which honestly very, very few people use, and nadofaragene, which people have not had the opportunity to use, I'm struck with your one year and your two-year high-grade recurrence-free survival rates of basically two out of three at one year and basically 50% at two years, which far exceeds anything that is currently FDA available.

So, I think one, everybody... with your work, with Dr. O'Donnell's work, with those that have been looking at this, clearly, this has become the de facto treatment of choice for those patients who are BCG unresponsive. Now, my difficult questions for you are this. Chemotherapy versus immunotherapy. For those patients who've responded, do you think ideally it's maintenance, or should it be once or twice a year exposure and if it comes back, then attack again with another induction course? What do you think we should do for those that at some point recur? Because there is a drop-off over time. It's not huge, but there is a drop-off. With those patients and I know it's small numbers, with those patients that have recurred, what has your strategy been? Because I would love to know what happens to those patients.

The initial one third that at one year has recurred, was it a trial? Did you try more? Did you do another induction? Et cetera. Have you had any salvage success with this regimen of those that have actually failed during maintenance?

Mark Preston: Right, that's a good question. So, I think obviously whenever we have... so these are patients that we're seeing typically in consult, BCG unresponsive, we have the discussion of early cystectomy and then either if we have clinical trial options open or this gemcitabine and docetaxel combination, which I think is a favorable choice. I don't think you're losing much time if you're... typically, if they're a new patient to me, it'd be a repeat resection, make sure we've got a good understanding of the bladder and the disease that's present, give them an induction course and then six weeks after that, typically a cystoscopy biopsy, see if there's residual cancer or not to see about ongoing either early cystectomy or if they're able to get it, or ongoing maintenance.

I do think there's a benefit to the maintenance therapy. I think there's not fantastic data, also retrospectively, whether you do monthly for 12 months, monthly for two years, it's been well-tolerated, and once a month treatment is pretty easy from a patient perspective. So, we have been doing that.

In terms of where you go beyond that, I've done repeat induction in a handful of patients. I wouldn't say with fantastic success. Some have been patients who couldn't have cystectomy for whatever reason, weren't keen on pembrolizumab, and we didn't have anything else available. I'm hoping to get the nadofaragene shortly. In theory, we're just trying to sort out the billing aspect for it, and then hopefully that'll be another option for patients. That seems to be, I think around 25% at one year. So it's good but very well tolerated. If you can give medication that you can give once every three months for four doses and tolerate like it is, I think it would be a good option.

Dr. O'Donnell actually also has some pretty interesting data looking at valrubicin and docetaxel, slightly different mechanism of action that was pretty good in those patients who had not responded to BCG, not responding to gemcitabine and docetaxel. We've been working on having that open as an option as well. But we're big fans of clinical trials here. Anytime there are various agents that are coming available in this space, we want to be able to have them open and available for patients as well. I think it moves the field forward and it gives patients options as well.

Sam Chang: And then how about those patients, because clearly we've had patients respond just as you have, what do you do at the one to two year mark? Do you deescalate the maintenance? Do you go to... to be honest, with no evidence behind it, I deescalate. If they haven't had disease for a year, 18 months, I deescalate and I go to honestly once a quarter. And then after a year, I'll go to...

Mark Preston: So we actually stop, so at that point... I've got some patients who always... sometimes there's a comfort factor to having some treatment. But the other practical logistical aspect of it is that this takes a fair bit of clinic time. We've optimized it as well as we can, but initially, the first treatment is an hour and a half in clinic with a catheter and then waiting that out and putting in the next one, it's not as fast as the BCG where you get into treatment and leave. Dr. O'Donnell's actually got some good data now that similar outcomes with one hour of treatment and then switching over.

So we typically have a Friday when we might do 18 patients within our gem/doce clinic, and now we're enrolling in the BRIDGE trial. We've got about 17 patients on that now. Max Kates's trial of BCG versus gem/doce in the high-risk naive setting. A lot of patients are looking for a gem/doce at the moment.

Sam Chang: Yeah, no, I think that'll be very important, and to me, it will be fascinating. They have reported on some signals that it may be just as good as, if not even better. To me, I think there are some zealots who think chemotherapy shouldn't work long term, etc. And at this point, I'm really excited about the future clinical trials that you've mentioned. And so, I applaud you, Mark, for all the work that you've done. Tell us here in a short little bit, what's your next exciting project?

Mark Preston: What we're working on here is I'd love to be able to do an actual randomized trial of gemcitabine and docetaxel. It's something that's, I think, hard to get funded, but I think has got value for it. It'd be nice to have prospective trial data that you can present to patients.

Short of that, I think the studies where... whether it's biomarker-based ones to try and determine which patients are going to respond to the various treatment options that we have, I think is going to become increasingly important now. Do you look at circulating tumor DNA either in the blood or in the urine or other signals to decide a BCG didn't work, if that was available, what would be the good next step for you? I think that area is super exciting, and I think now with even looking at some companies looking at the AI on path images, like your arterial AI for prostate cancer risk, I think looking at the actual... the slides as well in a different way might also help predict. I think it's an exciting time.

I think what's really exciting also is all the institutions and the young fellows and the young attendings who are getting into clinical trials and want to participate, I think has been fantastic for the field. And who wins with that is the patients, but all of a sudden, no matter what institution you're going to, there are multiple trials open, which wasn't the case even when I was a fellow. And so, I think over the last 10 years, that's probably been one of the biggest bright sparks, and I think continuing to cultivate and encourage that is important.

Sam Chang: No, I think a really good point. I mean, when I started doing this, when you were in diapers, it really is a big difference, and that growth and the expansion of studies, particularly in the areas that you talked about, is incredibly exciting. So Mark, thanks so much for spending some time with us, and look forward to doing it again in the future.

Mark Preston: Yeah, thanks very much for having me.