Transcript of What Do I Do If BCG Doesn’t Work with Dr. Michael O’Donnell

May 24, 2023

Listen to the podcast

Voice over:

This is Bladder Cancer Matters, the podcast for bladder cancer patients, caregivers, advocates, and medical and research professionals. It’s brought to you by the Bladder Cancer Advocacy Network, otherwise known as BCAN. BCAN works to increase public awareness about bladder cancer, advanced bladder cancer research, and provides educational and support services for bladder cancer patients and their loved ones. To learn more, please visit bcan.org.

Rick Bangs:

Hi. I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by, and about the bladder cancer community. I am also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it, BCAN, the producers of this podcast. This podcast is sponsored by the Seagen-Astellas Alliance. I am pleased to welcome today’s guest, Dr. Mike O’Donnell. Dr. O’Donnell received his MD from Duke University and was a resident in urology, clinical and research fellow, instructor, and assistant professor in surgery at Harvard. He is currently professor and director of urologic oncology at the University of Iowa. The author of over 150 peer reviewed manuscripts, 10 book chapters, and multiple reviews and abstracts, Dr. O’Donnell also serves on the editorial board of the Bladder Cancer Journal and the Journal of Urology.

He leads several national clinical trials using immune therapy to treat bladder cancer and holds patents in the genetic manipulation of BCG bacteria, and he was also a member of the BCAN Scientific Advisory Board. Dr. O’Donnell, thanks for joining our podcast today.

Dr. Michael O’Donnell:

Thanks, Rick. It’s a pleasure to be here and to talk more in depth about bladder cancer.

Rick Bangs:

All right, let’s get to it. So let’s start with a very quick introduction to BCG. We’ve had some other sessions on this, but I think it’s important to kind of set the stage. So let’s remind the listeners what BCG is and how it works in the context of bladder cancer.

Dr. Michael O’Donnell:

Sure thing. So BCG is a very interesting compound. It’s actually a live form of cow tuberculosis that was developed by the Pasture Institute almost a century ago for the purpose of developing a vaccine for tuberculosis. The bacteria was attenuated or weakened over 20 years of passage to the point that it could be given to humans as a vaccine against TB. However, it was noted at that time that patients that had TB and those patients that had wounds that were close to cancers had remarkable regressions or had less of an incidence of cancer. So the idea was floated around that maybe the immune system could somehow treat cancer. A very intrepid pioneer in the 1970s, Alvaro Morales from Canada, was working at the NIH, National Institute of Health, and discovered in his animal model of cancer that if he put BCG next to a tumor and the animal had a normal immune system and he gave repetitive doses that he could make the cancers disappear.

So when he returned back to Canada as a urologist and was encountering the difficult problem of carcinoma in situ, which is a surface spreading high grade cancer in the bladder, he had nine patients, at that time they were doomed to have their bladders removed, a cystectomy. But in seven of those nine people, after giving them six doses of BCG… it came as a six-pack, no joke, this is real… seven of the nine patients responded, and that started the whole story about using BCG to treat non-muscle invasive bladder cancer.

Rick Bangs:

So a lot of your research is focused on BCG, and in fact I think your career actually started with BCG, so can you summarize kind of the evolution of your focus across time?

Dr. Michael O’Donnell:

Sure. While I was a young urology resident in my research year back in Boston, a fellow across the river at MIT and discovered a way to genetically engineer BCG. He could put substances, genes, into BCG that would cause them to produce human proteins. At the time he was working to develop a better HIV vaccine. But it struck myself and my mentor, then Dr. William DeWolf, as a potentially clever way to make BCG better in its use for bladder cancer. And this led me into exploring the entire aspect of immunology and how BCG worked. And what we did discover was that certain substances that were immune, they were naturally immune potentiators such as cytokines or interleukins or interferons, could in fact make BCG up to a hundred times more potent as an agent. And so as I was pursuing that, we ran into a little bit of a stop because at that time the world wasn’t ready for genetic engineering.

No one wanted to sponsor genetic engineered BCG, and I was left with the idea that I knew that I could add certain things to BCG to make them work better, at least in the test tube. So I started a large clinical trial of BCG plus, at that time, alpha interferon. We enrolled 1100 patients, and these were patients from all parts of the NMIBC spectrum, patients for whom other therapy had failed, patients that were starting off for the first time, low-grade high-grade patients, and in this whole big mix we were seeing whether the interferon helped BCG and whether patients tolerated it. The long story short is that they did very well with it.

We were able to see positive beneficial effects in almost all of the patients, but we did notice that there was a resistance pattern to BCG that developed once patients had received at least two courses of BCG, and so this failure pattern, when BCG fails the patient, seemed to define a group that was unresponsive for which we should need to develop other therapy.

Rick Bangs:

And this is all back in the day when, this is before immunotherapy was hot, right?

Dr. Michael O’Donnell:

Yes. The big immunotherapy at the time was BCG, and then there was interleukin-2 that was used for renal cell carcinoma. We have moved way beyond that these days.

Rick Bangs:

Right, right. Okay, so let’s talk about the BCG failures because I think there was some work that you did that kind of triggered some discussion about how to categorize the failure of BCG in patients. So tell us about that.

Dr. Michael O’Donnell:

Well, a group of us, back about 10 years, that included Colin Dinney, myself, Mark Schoenberg, Ashish Kamat, and several others, big names in bladder cancer, met at the AUA to hash around the idea of what did it mean to be a BCG failure because there were so many ways you could define it. Did the BCG fail after just six treatments? Did it fail during maintenance therapy? What if it failed three years later? Was that the same as someone who failed immediately? And fortunately, the data that I had collected from this large national trial of BCG plus interferon had all sizes and shapes of patients with different histories of BCG exposure.

And it was through that I was able to work out what defined a class of patients for whom further BCG was likely not to be successful. And the FDA actually used our data-driven model for predicting BCG unresponsiveness as setting up the circumstances for which to do the later single arm trials in carcinoma in situ that have seen such a large amount of interest by various pharmaceutical groups.

Rick Bangs:

The sample here was large enough that you could actually see these categories. I mean, they made sense, right?

Dr. Michael O’Donnell:

Exactly. We had an incredible… I was at the right place at the right time, 1100 patients from 120 sites throughout the country, 80% from community sites. We got all of these patients within two years.

Rick Bangs:

Wow, wow. Okay, so now a little bit of education here. So we hear BCG, we hear it’s a pretty effective drug, but it’s not used in muscle invasive, but immunotherapy, the different immunotherapies are. So BCG, which is an immunotherapy, isn’t, but other immunotherapies are successful. So why are we not using BCG and in muscle invasive?

Dr. Michael O’Donnell:

It’s actually been tried, Rick. If you recall back to our great Canadian Alvaro Morales, in his studies he found that you had to have direct contact with the tumor to the BCG and it had to be small enough that the immune system could take care of it. Unfortunately, muscle invasive bladder cancer has deep roots to it and the BCG doesn’t penetrate. There was a small study of 10 patients with muscle invasive bladder cancer where BCG was tried, but seven out of the 10 relapsed with worse disease than when they had started, and that basically killed that whole approach.

Rick Bangs:

So why is it so hard to replace BCG in the non-muscle invasive space?

Dr. Michael O’Donnell:

Well, BCG is frankly an extremely good drug. Approximately 70 to 80% of patients respond immediately to the first six-week treatment. There’s a small drop off after that, but usually by two to five years, two thirds of these patients remain cancer free. Now, we did have a lot of other agents that we could put in the bladder, namely forms of intravesical chemotherapy, but none of them… with the possible exception of mitomycin for intermediate risk disease, so low-grade disease… could come close to approaching what BCG gave in terms of its initial effectiveness and its long-term durability.

Rick Bangs:

So pretty hard to replace something that does such a good job.

Dr. Michael O’Donnell:

Exactly. You would need studies where you have hundreds of patients to compare the two together.

Rick Bangs:

Right, right. So in recent years, I think you’ve moved away from BCG a little bit, so tell us why that’s happened.

Dr. Michael O’Donnell:

Well, I got as far as I could by adding immune stimulating components to BCG, and we still have a working model where we had BCG plus interferon, plus interleukin-2, plus a substance called GMCSF that stimulates the dendritic cells or the cells that break apart the BCG and expose it to the immune system. All of these things worked well, but they only gave small incremental improvements in BCG, and even to this date, we don’t even know exactly how BCG works. Our best thought is that it’s like a swarm of killer bees are brought into the bladder once the tuberculosis vaccine is put into it. It’s not enough to cause sickness in the vast majority of patients, but it’s enough to cause this swarm of white blood cells that come in and they indiscriminately attack every place where there’s BCG. It just so happens that cancer cells are not able to resist this form of attack, whereas the quiet normal cells are. So it’s a local phenomenon, but it is an immune mediated phenomenon, but it’s not directed specifically at the cancer. It happens to be, I call it a non-innocent bystander.

Rick Bangs:

Okay. So how’s the shortage impacted your work in the BCG space?

Dr. Michael O’Donnell:

Well, it’s been a major problem. You see, there used to be two large pharma groups that were making BCG. One was Canada, it was in Canada and it was going by the name of Connaught. It held about a third of the US and Canadian market. And then there was the Tice strain of BCG which at that time was part of Sanofi’s group. There was a fungal contamination that happened at the plant in Canada. What you have to understand is they literally grow this living bacteria in these giant hundred gallon vats, and if any kind of contamination got in there they’d have to shut down the whole thing.

In 2012 that happened, they never reopened. This now put the onus on Sanofi that was later acquired by Merck, who then had to basically cope with the fact that they had to increase production because other strains had also sort of gone by the wayside, and so they were providing the majority of BCG for the entire world, not just the US but most of Europe as well. That put on such a strain that it peaked in 2019 when we received letters from Merck saying, “We’re doing the best we can. There’s going to be delays. We’re going to give an allotment based on how much BCG you’ve used in the past, and you’re just going to have to deal with it. In the meantime, we’ll build some new factories.” But it won’t be until close to the end of this decade that they’ll be online and ready to produce.

Rick Bangs:

Wow. Okay, so now we’re going to divide the discussion from this point into two sections because it’ll be easier to digest what we’re going to talk about. And so the first section is going to be about frontline or first line setting, which essentially means this is the first treatment that’s being used to treat a bladder cancer before any other treatment. So this next section is going to be about that. And then we’re going to circle back and we’re going to talk about later use after this initial setting. So in this first line or frontline setting, what alternatives to BCG are there for patients because they haven’t had any other treatment, what other alternatives might there be for patients in this space?

Dr. Michael O’Donnell:

Well, Rick, as you recall, I mentioned that we had chemotherapy treatments that could be going into the bladder and mitomycin was the strongest, and it had comparable efficacy for the intermediate risk patients, those that had multiple low grade non-invasive cancers essentially. It didn’t work great for the stage one, early invasive high-grade cancers, so-called T1 cancers. It didn’t work well for carcinoma in situ. And so people have basically turned to that as the next available option. Fortunately, there were a couple of other drugs that came on the scene, most notably gemcitabine, also a drug that was used for intravenous therapy and used to treat advanced bladder cancer systemically. It was reformulated to be used in the bladder and we saw decent activity on the papillary tumors, even the high-grade.

But again, poor results for carcinoma in situ. In fact, there hasn’t even been much of any published literature on the use to replace BCG upfront. The only real agent that came to fore was actually something that we developed here at Iowa. You see, at the time when I was reaching the end of what I could do with recombinant BCG and cytokine enhanced BCG, I started looking at why we were giving single drug chemotherapy in the bladder. It didn’t make any sense to me because in every other human cancer that we treat with chemotherapy, we use multiple agents with the idea you have a one-two punch coming from different directions in order to strike different vulnerable points in the cancer’s lifestyle.

So the problem was all of the older chemotherapy drugs such as mitomycin, adriamycin, epirubicin, they were called vesicant drugs. They were the type of drug that if you had an intravenous infusion for systemic chemotherapy, if it leaked from the vein you had horrible tissue reactions. It caused massive problems. And so it was no wonder that all of the side effects that were attributed to those diseases, those drugs when we put them in the bladder, were basically related to direct tissue irritation such as cystitis, chemical cystitis. Well, gemcitabine came along, it was the first non-vesicant drug that didn’t cause this problem so patients tolerated that extremely well. And then the taxanes, the same drugs that were basically a huge boon for advanced breast cancer.

You may recall a Pacific yew tree, extracting the needles and so forth, and docetaxel emerged as one of the strongest agents there. That one is also a non-vesicant, and so it would cause almost no cystitis reaction in the bladder. Well, we first started out with gemcitabine and mitomycin because at least we could do no worse than that. We got really good results. However, then what happened was that mitomycin went into shortage and docetaxel was just being studied. So I said let’s substitute docetaxel for mitomycin and we came up with the gemcitabine/docetaxel, or as we call it now, the gem/doce Program. When I started off using this program, I used it primarily for patients for whom BCG had failed, and we were getting 50% of those patients cancer free at two years, which was remarkable. No one else had anything even close to that.

But a few patients along the way couldn’t get BCG, either they were allergic or they had a kidney transplant or a heart transplant and they were on immunosuppression, or they were elderly over the age of 80, or diabetic. All conditions for which BCG doesn’t work very well. Most people don’t realize that, but there’s a 50%, or let’s say a 33% decrease in effectiveness for patients over the age of 80, diabetics, that are given BCG for their bladder cancers.

Rick Bangs:

33%?

Dr. Michael O’Donnell:

Yes. So a BCG in a normal, healthy, 75 year old would have a 60% rate at two years of being cancer free. That rate dropped to 40% if they were either diabetic or they were over the age of 80. So I had a number of patients, about 30 patients, who I gave the gem/doce to, and remarkably over 80% of them were cancer free. Well, fast forward to 2019 when the BCG crisis hit its maximum point of shortage, and I had patients that were coming into the university referred from all the outside practices where there was no BCG, and they had heard we still had some BCG at our place. When they came, I couldn’t keep up with it. I switched them all upfront to gem/doce. In this way, we got 107 patients within about three years, we were able to publish our first major paper on the use of gem/doce for BCG naive… they’ve never seen BCG… high risk high-grade patients.

Remarkably, this was published in the September issue of The Journal of Urology last year. 82% of the patients at two years were cancer free, 84% were free from any form of high-grade cancer. The two-year cancer specific survival was 100%. Not a single patient progressed during that time, and less than 4% of patients had to drop out because of side effects. For BCG it’s about 10%. So we knew we had hit a winner, but still there have been a lot of people that have basically asked for more. This was what’s called a retrospective study, a study that we looked back at the patients we had treated and we had a very comprehensive protocol for doing everyone the same way, but we didn’t have a comparison to BCG.

Fast forward to February of 2023, we were able to take the last patients, all the patients that were treated with high-grade BCG naive disease, either with BCG or with gem/doce and compare them. They were very similarly matched cohorts, but they were not randomized. But despite this, we were able to show that gem/doce was not only better tolerated, 3% dropout versus 9% with BCG in this comparison, but at every single time point from one year, two year to three year, gem/doce was actually superior to BCG in preventing the reemergence of high-grade cancer.

Rick Bangs:

If you had proposed a clinical trial and stated the objectives, which were your outcomes here, people would would’ve thought that was a very, very aggressive goal.

Dr. Michael O’Donnell:

It would’ve seemed risky, but the BCG shortage actually allowed this opportunity, because here we had people that had nothing else that had really much of a chance of working. We had had preliminary results in 30 patients showing very good results. I individually talked with each and every person who went on to get the gem/doce and told them, “This is where it is, and we don’t have enough BCG for you.” And every one of them said, “Let’s go for it.” And I have to give them all a big praise for being so courageous, because without that kind of bravery we wouldn’t be where we are today.

Rick Bangs:

No, absolutely not. So the mechanism, the way these things will work, gem/doce versus BCG, I get the sense that we’re no longer dealing with these angry but productive bees in the gem/doce setting. This is different.

Dr. Michael O’Donnell:

Yeah, I tell people that bladder cancer is like having weeds in your lawn. The deeper ones are your invasive cancers. The shallow ones are like carcinoma in situ. You can either pluck them out, which is surgery, but they always come back. Or you can use an organic formula, which is like BCG, and try to make your lawn as healthy as possible, or you can revert to ChemLawn and basically throw the chemicals on it that are contact poisons for the weeds you want to kill. And that’s basically what gem/doce does. The gemcitabine has been shown to actually not only cause a cancer effect in itself, but it sort of scrapes off the inner surface of the bladder and it allows then the docetaxel to go deeper inside. In fact, two to three times as much will penetrate the bladder if they’re pre-treated with gemcitabine. So this formula seems, and I can’t say that I knew in advance that this would work, but a discovery is enhanced by the right circumstances and a prepared mind, and I was there at the right time.

Rick Bangs:

Wonderful, wonderful. Okay, so how do you decide that a first line treatment has succeeded or failed the patient? And I love the fact that you’re talking about things failing the patient because patients never fail treatments, treatments fail them. So how do you decide that something has succeeded or failed for the patient?

Dr. Michael O’Donnell:

In the sense of the medical and scientific community, you really need a prospective randomized trial that unequivocally accounts for all the biases that you could have introduced in looking back at the patients you’ve treated in the past. And fortunately, Max Kates at Johns Hopkins University, also one of the first users of the gem/doce that validated our studies, has started a large trial, over 800 patients, that will take patients with high-grade disease that have never been exposed to BCG and randomized them to BCG versus gem/doce. I encourage all of the patients listening to this podcast to strongly support this because this is the only way we will know for sure if this is equivalent or if gem/doce is in fact better than BCG. Now, in terms of following the patients, how do you know that they’ve recurred? Of course, it’s the simple you look in the bladder. In my case, every patient with high-grade disease gets an extremely thorough investigation at the first three months, because in my opinion, you want to know as soon as possible did this treatment work or not?

So the average urologist just looks in the bladder in the office, takes a urine sample, send it for cytology, and says, “Yeah, I think it’s probably working.” However, what we do, every patient comes in under anesthesia, they get a blue light cysto to look for any suspicious lesions. They get automatic biopsies of anything suspicious plus random areas of the bladder. We also take biopsies from the prostate area where the urine passes through because about 10% of recurrent cancers tend to lodge there. And we check the upper tracts of the right and left kidney with washings to make sure there’s no trace of any cancer. Only then do we let the patients pass on to what we call maintenance therapy, which in the case of gem/doce is once a month for two years.

Rick Bangs:

So if a patient was looking for the Max Kates trial, Dr. Kates has been a podcast guest, his last name is K-A-T-E-S, and there’s an acronym for this trial that I can’t remember.

Dr. Michael O’Donnell:

It’s called the BRIDGE Trial. It’s basically BCG versus gem/doce, with a lot of stuff in between.

Rick Bangs:

Yeah, yeah, exactly. Okay, so that should get our audience there if they’re interested in looking for that. All right. So what’s the pipeline for these BCG alternatives looking like for first line treatment?

Dr. Michael O’Donnell:

Well, once we had defined a BCG unresponsive space, remember that goes back to that old trial of BCG plus interferon, the FDA was looking to see if they could streamline a way to bring new drugs to market, because we hadn’t seen much movement, scientific and clinical movement, in the last 20 to 30 years since BCG was created or was utilized. It turned out that for the first time the FDA started to consider single arm relatively small trials. So as before, most large trials in bladder cancer were using hundreds of patients that were randomized between two arms, arm A and arm B. One of them was probably what we were currently using, one was the new therapy we were going to trust. However, in the case of carcinoma in situ, the surface disease, we know that we cannot surgically remove it.

It is like those weeds that are so flat and have little pieces, you pluck them off and there’s always stuff left behind. So they agreed that if we have enough patients, a sufficient number, and they agreed that something like a hundred patients, if we could show that new drugs could actually cure this disease by making it completely go away, then that was felt to be unequivocal evidence of an active cancer agent. And that opened the door for a wide number of new developments. Let’s go through some of them. Let’s go through with the first one, a new drug that was approved for the last 20 years, and that was the Merck drug called Keytruda or pembrolizumab. This is a drug given for advanced cancers, and in about 20 to 30% of patients the results can be miraculous, even patients with metastatic disease.

So considering the choice after BCG failure was cystectomy, they felt this was a reasonable drug to try it in. And it got FDA approval because 41% of the patients had a complete response to the treatment. However, at one year it had already reduced to about 19%, and by two years it was down to 11%. So even though it’s out there, it’s available, it’s FDA approved, urologists are reluctant to use this drug both for the fact that the efficacy dwindles with time and secondly, there are immune related reactions that can be quite severe, including activating the immune system. We talked about the killer bees, well, imagine your immune system is so activated that it attacks your heart, your lungs, your skin, your thyroid, and multiple other organs. That happens in about 10% of cases.

So that one didn’t really catch muster, at least not in today’s world. The second one that was just approved January of this year, is a drug called nadofaragene and the code name is Adstiladrin. It’s a genetically engineered virus that produces interferon. And the interesting thing about it is, whereas we were using interferon that we’d put in the bladder, within two hours it was pissed away. And so it never stayed around long enough for it to have a really significant effect. This virus actually causes the bladder to produce its own interferon at extremely high levels for over a week. The net effect of that is that you only need to get treatment once every three months. The downside is it’s not a home run winner, but about 25 to 30% of patients are cancer free one year later with CIS.

Now, there are a lot of new drugs. There’s another virus that has similar effectiveness. It only targets cancer cells, which makes it a more attractive feature, and it produces this substance called GMCSF, which remember I told you activates the body’s immune processing system so that it makes proteins from cancers more immunogenic. So that one looks good. There is what we call the chemical pretzel, which is developed by a group called Targis that has impregnated these, they’re kind of like stents except you put them in the bladder and they curl in the shape of a pretzel and they release long-acting agents of gemcitabine or other single chemicals, so far. There is a hypothermic therapy program that takes mitomycin and increases effectiveness by over twofold by heating it up to 43 degrees on the inside, either with microwave or a conductive heating solution, that looks really good.

And there’s even a gel form that that may have effectiveness in this area. So there’s a lot of exciting activity in this realm today. But so far, with gem/doce leading the pack at 50% complete response rate maintained at two years after failure of BCG unresponsive patients with CIS, it’s still the leader with one exception. And this gets you into the next drug that’s up for FDA review, which is something called N803 combined with BCG. So N803 is a synthetic form of another immune stimulating agent called interleukin-15. They’ve modified it so it stays around a lot longer and it activates natural killer cells, and it decreases what are called repressor cells at the same time. So it basically augments another form of the immune system to come in and do the work that BCG failed at.

In their studies, and I’ll tell you it’s a little harder to interpret because patients were given two chances at getting the drug, but the first time they got it 54% completely responded to CIS, and half of those patients, a little under 30%, were cancer free two years later. But if they allowed the patients to get a second course of N803 and BCG the results were very similar to gem/doce, that is 71% responded immediately, 60% remained in response at one year, and about 50% remained in response at two years. So that’s a really exciting contender for patients with BCG unresponsive bladder cancer.

Rick Bangs:

This whole space is so different. I think I met you in 2010. I think that’s when we first met. And at that time there was nothing that was anywhere near as exciting as this.

Dr. Michael O’Donnell:

No, not at all. In fact, bladder cancer for the longest time was like your third cousin twice removed. Nobody knew about it. And I’ll credit the FDA by being so creative in their thinking, by opening these one-armed relatively small trials, it encouraged a lot of new interests from pharmaceutical to look into bladder cancer. That made all the difference in the world.

Rick Bangs:

Yeah, yeah. They’ve evolved to a much better place and it’s helping us in our space so that’s great. So let’s talk about the toxicity, because you’ve mentioned it a couple times in this conversation. So as drugs get moved down from muscle invasive into non-muscle invasive, which is what we’re talking about today, what do patients need to know or consider relative to toxicity?

Dr. Michael O’Donnell:

Well, they need to ask. So let’s take the case of Keytruda, pembrolizumab, that drug for most people hardly causes any problem. However, in 10 to 13% it can cause these severe immune reactions which need to be monitored, and usually by medical oncologists that are used to it, because if they’re ignored patients can die from the side effects. So that’s clearly a major concern. The viral drugs seem to be very safe. Even though they’re genetically engineered, they’re modifications of existing viruses that we as humans have been exposed to all our lives. So that looks pretty good. They just cause some minor bladder irritation. The new chemotherapy drugs, the non-vesicants like gemcitabine, docetaxel, practically cause very little bladder irritation. In fact, half of my patients report no side effects whatsoever.

The others have pretty minor, a a little bit of tiredness for a day or two, a little burning the first couple of times they pee, occasional case of nausea easily controlled by a medication, and that’s basically it. The hypothermic treatments caused much more bladder irritation initially, and then they calm down later after that. So a lot of things you need to know, but patients need to ask specifically what’s the chance I’m going to have a side effect? What’s it going to feel like? How long is it going to last? Am I going to recover completely from it or will there be some long acting consequences?

Rick Bangs:

Okay, so now as we segue into the second space, so there’s different types of failures by BCG, so let’s talk about what those are. Just remind the audience some of the failure types as we talk about getting these second line or treatments on top of treatments.

Dr. Michael O’Donnell:

Sure. So as patients that have had BCG understand, the first time you get BCG you usually get it once a week, six in a row, and then you’re evaluated to see if it worked worked. If it worked you get what’s called maintenance therapy, which are usually mini boosters of three treatments each every three to six months for up to three years. The BCG shortage has really curtailed that, and now people are getting lower doses, and many doctors and urologists have had to omit maintenance therapy. But then there’s also something called reinduction, which is like when I mentioned N803, when BCG fails once it usually has about a 60% effectiveness. A second time it’ll have about half that effectiveness, maybe 30 to 40%, but it’s certainly worth a second try.

So those people then, if they fail… if the BCG fails them, I should say… after two courses of BCG, especially if they’re within one year of one another, or if it fails during active maintenance therapy, then they enter the BCG unresponsive category where further BCG only has about a 20% chance of giving a long-term remission. And that’s the reason why these new drugs are necessary in this BCG unresponsive space.

Rick Bangs:

Okay, so now we’re going to introduce a new term, which is one when you first mentioned to me I really liked this term, so what’s a rescue treatment?

Dr. Michael O’Donnell:

Well, the old style term used to define a new maybe less thoroughly researched treatment after BCG had failed was called salvage treatment.

Rick Bangs:

I hate that term.

Dr. Michael O’Donnell:

Yeah, who wants to be thought of as a piece of salvage, right? So I thought it made much more sense to coin the term rescue therapy, because that’s exactly what you’re doing. You’re giving the patient a chance to reclaim the bladder health that they deserve to get rid of the cancer. Now with this, however, also comes the danger of what if you wait too long? Because, Rick, if you pursue a course, especially multiple courses of rescues, eventually, if the cancer’s particularly aggressive and not responding, then those patients may progress to muscle invasive disease, which is a life-threatening condition. So we think there’s about a two-year window of patients to get a rescue therapy before it’s time to start looking into the more surgical alternatives.

Rick Bangs:

Okay, so now you’ve talked a lot about these exciting possibilities in the first line setting, and so now after this initial treatment what alternatives are there in that setting? And I’m assuming some of them are the treatments that we’ve talked about previously, but tell us what’s happening in that space.

Dr. Michael O’Donnell:

Yes, and let me clarify that the only drug that has been thoroughly tested as an alternative to BCG in the frontline setting is gem/doce. There are no large studies of gemcitabine. We know from the historical that mitomycin was worse than BCG, so we know that. But all of the other agents have not been tested in the frontline setting. So everything I told you about in terms of N803 with BCG, of the Targis gemcitabine pretzel, of the viral modified virus attack complexes, those are all for patients that have become BCG unresponsive. Now, each of those companies that has developed these is looking to move this into the pre BCG exposure state.

The trouble is, again, even to show an equivalence to BCG, you need 800 patients. 400 getting BCG and 400 getting the new therapy. And there haven’t even been phase two studies in BCG naive space. Some of them are undergoing right now, so we’re we’re way behind in terms of finding a substitute for BCG as upfront therapy, the one exception being the strong data that we’ve been able to generate on gem/doce.

Rick Bangs:

And 800 patients, just to frame this up for our audience, 800 patients on a clinical trial, that’s a lot of patients. That’s a lot of time to get up to 800 patients.

Dr. Michael O’Donnell:

It’s predicted that the BRIDGE trial, that it’s going to compare gem/doce to BCG, is going to take at least three years, maybe four years, to get the 800 patients and then every patient will be followed for at least two years afterwards. So it’s going to be about seven or more years before we have the answer to whether one is better than the other.

Rick Bangs:

Okay, so let’s talk about today when BCG fails a patient, because I just want to peak and kind of summarize here, what’s the next step when a patient is failed by BCG today? What’s the next step?

Dr. Michael O’Donnell:

Well, the discussion should always begin with the historical choice and the standard of care is to do a cystectomy. But I will tell you from talking directly to patients… and I recall one particular conversation. I told a patient who had failed from getting BCG, and they failed twice, and they had a small area of carcinoma in situ the size of a postage stamp, and he asked me to describe what I actually saw. And then he said, “No. You have something the size of a poster stamp, it’s not invaded, and you’re telling me that you’ve run out of things to do. I want you to come up with something that works better.” And I said, “Well, I’ve been working on this new drug,” and hand goes up, “I want it.” I said, “Well, I’ve used it on one patient and it worked.” And they go, “I want it, I want it, I want it, I want it.” And then finally you have enough people that you’ve tested it on and you say, “Wow, this stuff really is working.”

So consider gem/doce. Now, I will tell you in the academic circles, 70% of the academic urologists that work professionally with bladder cancer are using gem/doce. However, in the community only seven to 8%. And the reason for this is a combination of not being aware of it, and also the fact that it takes a longer period of time to give the gem/doce. You’re giving two drugs, they can’t be mixed together so you have to give one for an hour and a half with a catheter and a plug on it. Then you unplug it, you put the second drug in, and then you can pull the catheter much like we do with BCG, and the patient can go home. But that means for a doctor that is moving patients through their office every 15 minutes, suddenly you have to occupy a room for one and a half to two hours. Well, that doesn’t sit well with community urologists, and so many of them don’t even want to look at the idea of giving combination therapy.

Rick Bangs:

And I’m guessing insurance reimbursement is not what it might be to the clinician in the community either.

Dr. Michael O’Donnell:

It’s reimbursed at the same rate as a single dose of chemotherapy, not accounting for the extra time that’s put in, so that’s exactly a problem, yes.

Rick Bangs:

Yeah, yeah. So any final thoughts on this space or this whole conversation?

Dr. Michael O’Donnell:

Well, I would tell people to stay tuned. Look at what’s going on. One great site is clinicaltrials.gov. It tells all about the new treatments that are being investigated for bladder cancer. Certainly BCAN is an amazing resource of new trials and where they’re happening. The patient resource that BCAN has is another great way for people to talk to other people that have tried a therapy. They can tell you about the side effects and whether it’s working for them. So stay tuned. Make this an investment in yourself and your health the same way you would do for your retirement. You’ve got to basically have a forward-looking active role in this process.

Rick Bangs:

Yep, absolutely. We need empowered patients here. Dr. O’Donnell, thank you so much for giving us this great understanding of BCG and BCG alternatives, and what the future holds for us.

Dr. Michael O’Donnell:

It’s my pleasure, Rick.

Rick Bangs:

If you’d like more information on bladder cancer, please visit the BCAN website, www.bcan.org and search BCG. And in case people wanted to get in touch with you, could you share a mechanism where they can get ahold of you?

Dr. Michael O’Donnell:

The best way would be to go to the University of Iowa Healthcare website, and we’ve got some very interesting stories about our development of gem/doce there, and certainly information about our bladder cancer and our urologic program in general.

Rick Bangs:

Wonderful. Just a reminder, if you’d like more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at 1-888-901-2226. That’s all the time we have today. If you liked this podcast, never miss an episode by clicking on the subscribe button on your favorite podcasting platform. And remember, rating our podcast also helps us reach more people and feel free to leave a review as well. Thank you for listening, and we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. O’Donnell.

Dr. Michael O’Donnell:

It was a pleasure. Take care.

Voice over:

Thank you for listening to Bladder Cancer Matters, a podcast by the Bladder Cancer Advocacy Network or BCAN. BCAN works to increase public awareness about bladder cancer, advanced bladder cancer research, and provide educational and support services for bladder cancer patients. For more information about this podcast and additional information about bladder cancer, please visit bcan.org.