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Transcript of Bladder Cancer Matters Episode 1: What’s the Deal with Bladder Cancer and BCG?

Below is the transcript from the “Bladder Cancer Matters” podcast, episode 1.  The guest is Dr. Ashish Kamat of MD Anderson Cancer Center and the host is Rick Bangs.  They discuss BCG, or Bacille Calmette-Guerin, in bladder cancer treatment.

To listen to the episode, please click here.

Voice intro:

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, advances 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, my name is Rick Bangs, and I’m the host of Bladder Cancer Matters. A podcast for, by and about the Bladder Cancer Community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year a neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it BCAN, as well as several other organizations. This podcast is produced by BCAN, the Bladder Cancer Advocacy Network. In these podcasts, I interview bladder cancer patients, survivors, caregivers, and medical and research professionals to bring our listeners insight into topics of interest to the Bladder Cancer Community. Today’s episode is brought to you by FerGene, a gene therapy company dedicated to creating and delivering innovative solutions to urologists and those infected by non-muscle invasive bladder cancer. We are grateful for their support.

Rick Bangs:

I am pleased to welcome our inaugural speaker, Dr. Ashish Kamat. Dr. Kamat is a professor of urology and Director of Urologic Oncology Fellowship at MD Anderson Cancer Center in Houston, Texas. He is also a member of the Bladder Cancer Advocacy Network Scientific Advisory Board. Dr. Kamat expertise is in multidisciplinary management of urologic cancers with an emphasis on bladder and prostate cancer, bladder sparing therapies, minimally invasive techniques and bladder replacements like my neobladder. A major focus of his research is to develop novel treatments for bladder cancer, and identify resistance mechanisms and ways to overcome them. Welcome Dr. Kamat.

Dr. Ashish Kamat:

Thank you, Rick. It’s a pleasure to be here with you.

Rick Bangs:

In today’s episode, we’re going to talk about alternatives to BCG treatments, given that the treatment has been in short supply for some time and BCG does not provide acceptable results to all patients. Patients have been extremely frustrated by what is the third shortage in less than 10 years. From the patient perspective, it does not look like anyone is planning for and ensuring adequate supply. If there were great BCG alternatives, these shortages would be easier to manage and accept. Unfortunately, BCG remains the strongly preferred treatment given its effectiveness. As was true with previous shortages, patients and their doctors have sought alternatives. We will talk about some of these alternatives today. BCG is always a hot topic of conversation in the Bladder Cancer Community. So let’s start with some basics. Dr. Kamat, what is BCG and how does it work?

Dr. Ashish Kamat:

Very important question, Rick. When you consider BCG, people often mistake it for chemotherapy. And it’s important for folks to recognize that BCG accessingly is a mycobacterium. And the BCG stands for a Bacille Calmette Guerin because it was developed from the tuberculosis bacteria as a vaccine against tuberculosis many decades ago. It’s a very potent immune stimulant, and it’s actually an immunotherapy. And to be honest with you, even despite the recent advances and the news media and all the press that you see about the new molecules, not just for bladder but all cancers, BCG really is the most effective immunotherapy in oncology period.

Dr. Ashish Kamat:

The reason as you mentioned earlier, many patients don’t derive adequate benefit from BCG unfortunately, is because it’s not used appropriately. And we can touch upon that I’m sure over the course of the next several minutes. But coming back to your original question, it’s an attenuated bacteria that was developed as a vaccine against tuberculosis, and it has been discovered to have multiple effects as far as stimulating the immune system’s concerned. So, from the perspective of a bladder cancer patient, it is a immune modulator, immune oncology agent to protect against bladder cancer.

Rick Bangs:

So you used the word attenuated. So, that means it’s been kind of neutralized?

Dr. Ashish Kamat:

Yes. If you think about it… If you inject anybody with the actual tuberculosis bacteria, you are infecting him or her with the bacteria. And when the vaccine was developed, it was developed in such a way that the bacteria was attenuated and not completely killed, but almost made to a point where it generates the immune response, but is not able to replicate adequately on its own. Now you probably remember or you may have heard about the disasters that occurred early in the course of humanization against tuberculosis during the World Wars, and that’s partly because some of the vaccine that was supplied contain in non-attenuated form, and that’s what led to actually people getting the vaccine actually getting tuberculosis. So yes, the BCG that’s used today, both against tuberculosis and in bladder cancer and also and I have talked about as our vaccine against COVID 19, is the attenuated form of the tuberculosis bacteria.

Rick Bangs:

Great. So, It works really well. So, why would there be a shortage?

Dr. Ashish Kamat:

Well, It’s precisely because it works so well that there’s a shortage of BCG. The global demand for BCG when it comes to bladder cancer is in excess of about a million doses required every year. Which means that if you had enough BCG, we could actually be providing patients with a million doses a year, just for bladder cancer. Now add to that the fact that BCG is required even today and is used extensively in many countries as a vaccine against tuberculosis, in newborns and the elderly, there’s a huge demand for BCG. But BCG is one of those drugs that because it’s been around forever, is really inexpensive. And hence the whole manufacturing process, the impetus to put in more infrastructure to develop BCG, doesn’t exist from a… To put it bluntly profitability standpoint, so there’s not that many people that are actually manufacturing BCG. So it’s a demand and supply. There’s a lot of demand for it, but there’s not enough BCG being produced for the reasons I mentioned and others. And hence there’s not on a BCG go around.

Rick Bangs:

So, is it expensive to manufacture? In other words, do you have to invest a lot of money in a plant to specifically produce the BCG?

Dr. Ashish Kamat:

Yes, that is one of the challenges that we faced in the United States for example, until the early 2010s, 2012 and 2014, there were two manufacturers of BCG, Sanofi and Merck. And Sanofi had some issues with having to redo their plant and renovate it, and long story short, the costs that went into doing that did not sort of in some ways justify the end result which was plant closed. And Merck has recently, in the last several months announced that they will be investing in developing additional facilities and additional plant for BCG production in North America.

Dr. Ashish Kamat:

But by the time the plant is up and running and it’s inspected and approved, it’ll be about four or five years I would guesstimate, and then after that another couple of years before BCG is up and running as far as production is concerned. Because it’s a slow manufacturing process. It’s not a molecule that you can synthesize in the lab. It’s actually the bacteria that has to be grown in culture on certain media, and certain types of potatoes, and it’s a classic technique. So it takes a while. And to get to the point of your question, yes, it is expensive and it’s tedious, and that’s why there not too many people jumping into the manufacturing process.

Rick Bangs:

And based on needing to build another plant. So Merck’s going to build some additional capacity and it’s going to take some time to build it, then it’s got to be inspected, they’ve got to get online and get approval. So, how long do we think we’re going to be in a shortage type situation?

Dr. Ashish Kamat:

So Rick, the shortage again, as I mentioned, it’s a relative shortage. There’s a shortage because we need a lot more BCG than is being produced at least for patients in North America and many parts of the world. But there are parts of the world where there is absolutely no BCG shortage. There are folks in Germany when you chat with them, they’re like… Oh. We didn’t even know, that this is an issue. There’s plenty of BCG in India, in Japan, there are manufacturing plants in many places in the world. So, when we’re looking at the approach, one of the things that’s actually happening and it’s a SWOG study that you’ve been very involved in, is to look and see if we can identify another strain of BCG that is available for example, the Tokyo strain, and confirm that it is just as good as the strain that’s approved in the United States.

Dr. Ashish Kamat:

And that’s more a regulatory question. When we say just as good we in the scientific community believe that it is, but of course the FDA needs to have proof. And one way to get around the shortage is to import BCG that’s available in other parts of the world and get over the shortage in that sense. But if you’re looking at the pure manufacturing process and we assume that Merck’s going to be the only one that actually jumps into the fray in the United States, I can’t believe it’s 2021 already, but add seven, eight years to it, and I think in 2030, we’ll be saying, “gosh! We can’t believe that it’s finally we are overcoming the shortage of BCG.”

Rick Bangs:

So on the SWOG study, we’re looking at a difference strain and strains… Or it’s not like it’s a generic version of a drug. A strain is a different animal. Right?

Dr. Ashish Kamat:

No, it’s the same animal, it’s a different breed. So, it’s almost like you have different puppies and you now have your designer puppies, and the thoroughbreds, and then you just have the average month that we all love. So, that’s pretty much what the strain is. It is the same bacteria, but because it’s been decades since the original bacteria was developed as the vaccine, and that bacteria were shipped to different parts of the world, the bacteria change, they mutate, just as you hear a buddy call developing resistance to antibiotics or becoming a different strain of equal high. But it’s still the same equal high causing the diarrhea. If you eat and don’t wash your hands, and when you’re traveling. The same thing with the BCG. It’s a different strain. It’s very similar, but yet different enough that you can actually identify it as a different breed. So it’s the same animal, it’s just a different pedigree.

Rick Bangs:

That’s fascinating. So, obviously we’re looking to bring a different strain here to the United States. What other steps are being taken to get us through this shortage? So we got new strain, we’ve got new production facilities that Merck is working on. What other steps are we taking, both in the short-term and the long-term to get us through the shortage?

Dr. Ashish Kamat:

So in the medium term… So we’ll go from the long-term which we just talked about and then the medium-term would be other companies, profit and nonprofit have been involved in this area and their attention has been raised. I know the Gates Foundation is very active when it comes to BCG, but that’s more as a vaccine for tuberculosis in underserved countries. But I do believe that they’re interested now in BCG per se, just period. There’s also the Serum Institute of India, which has been in the news recently because they’ve committed to producing close to a hundred million doses of vaccine against COVID-19. And they’re working with the Oxford Vaccine and the AstraZeneca and things like that. But they make BCG. And they also make a recombinant BCG which is a little quicker to produce and grow, et cetera, et cetera.

Dr. Ashish Kamat:

So that’s some potential avenues that we should be looking out for. In full disclosure am advising different groups, and different companies, and trying to get the whole community over the shortage. So I do have some of this inside knowledge, but I can’t share too much detail. When it comes to a more immediate as to what’s happening right now, well, the AUA SUO ASCO, all-day cancer groups per se, in and led by BCAN have put forward certain guidelines for physicians and patients to follow, to help us overcome the shortage.

Dr. Ashish Kamat:

Because again, it’s a demand and supply thing. So if we could, in some ways improve the supply chain, that would help. And one of the things to keep in mind is that BCG is so potent that not every patient needs that full dose of BCG. In fact, there’s been many studies and the European study was the most classic one that everybody quotes, where you can reduce the dose of BCG to one third and have almost exactly the same efficacy when it comes to progression of disease and a slight drop in benefit when it comes to recurrence. Which means for the average patient, there’s not much to be gained by going on a full dose BCG.

Dr. Ashish Kamat:

So, what many facilities including ours have done, is we’ve developed a way in which we can cut one vile into three doses, and that way we can provide three patients with BCG from one vile, rather than just give one patient a dose of BCG and then deny to others. And that’s happening in many other centers in the United States, it’s something that’s well recognized by all the organizations that I mentioned. And that allows us to, as I said, provide three times the number of patients with BCG, as opposed to if we didn’t do that.

Dr. Ashish Kamat:

The other thing that’s crucial is appropriate patient selection. Because what happens sometimes is that, we’ll find that patients who don’t need BCG are getting. In other words, someone’s use a cannon to kind of shoot a fly. A patient has a low grade tumor, it’s the first time tumor that’s been resected, and yes you can give BCG and try and boost the immune response, but that particular patient doesn’t need to have such intense aggressive therapy because he or she can really just have surveillance and may never have recurrence of their tumor. So, not giving or using BCG when it’s inappropriate, and when it’s appropriate, using it appropriately, are two immediate ways in which we’re trying to overcome the shortage.

Rick Bangs:

So, I hear some patients online talking about their doctor doesn’t have it, I hear other patients saying their doctor does have it, or to try another doctor because they have it. So, why would some doctors have adequate supply, but others don’t?

Dr. Ashish Kamat:

Rick, that’s been one of those mysteries that even though I and others have talked to the folks at Mecrk’s supply chain, it’s really hard to understand. I don’t believe it’s because they’re not doing it right. Because they have a way of doing it and what they’re saying is that they have decided on the allocation of BCG within the US based on previous usage patterns and also projected needs of the patients. So, what’s in theory happening is that, centers that have had a high demand for BCG are getting more BCG than centers that have not had demand for BCG. But even though that’s the party line, I have heard from cancer centers that, we used to have a lot of BCG and now we have no BCG.

Dr. Ashish Kamat:

So, it really is a distribution, and honestly I’m a little lost at myself to sort of understand why we, for example, at MD Anderson have a lot of BCG. I know Ochsner Clinic in New Orleans has even more BCG than we do, even though we need more BCG. But then there’s cancer centers in California right in the heart of LA that I’ve been talking to some of my investigators there they’re like… Oh gosh! We haven’t had BCG for six months. I really can’t figure that out.

Rick Bangs:

And the Food and Drug Administration, the FDA, doesn’t regulate this distribution across the institutions. Is that right?

Dr. Ashish Kamat:

That’s correct. The way it works with drug supply in the United States is that the FDA is responsible for regulating approval and safety, and of course post-marketing studies of that kind, but not the actual distribution.

Rick Bangs:

All right. So, if you’re a patient and you can’t get BCG today, what alternatives might you be offered and how effective are they compared to BCG?

Dr. Ashish Kamat:

So the first thing I would tell a patient that’s listening in is that, if you really have a tumor that’s aggressive and your other option would be a radical cystectomy, then it is worth seeking out a physician or a center that has BCG and getting BCG. Now, I totally understand that tribal constraints, economics things factor in. And if it’s not possible for you to go and seek out a center or a physician that has BCG and get the BCG, then there are alternatives. And the alternatives are essentially intravesical chemotherapy. Because I don’t really want to consider radical cystectomy as an alternative to BCG. Even though if you look at the published data, since there has been a shortage of BCG or the last decade or so, the number of patients undergoing radical cystectomy has grown up by 300%. And it’s hard to believe that it’s not because of the shortage. Right?

Dr. Ashish Kamat:

It’s not always a cause and effect, but the fact that there’s a shortage of BCG and now three times a number of patients are undergoing radical cystectomy would lead you to make the logical conclusion that, since there’s not BCG available, more patients are ending up having to lose their bladder. But if a patient can get BCG, great. If he or she can’t, then the alternatives that are available and approved right now are intravesical chemotherapy. And really what we use at MD Anderson and many centers have used this based on work that was initially pioneered by Michael Donald, five, six years ago, and now been shown in multi-center registry studies is a combination chemotherapy of gemcitabine and docetaxel. That’s the combination that we tend to favor, but to be honest with you, combinations of mytomycin and docetaxel or mytomycin and gemcitabine, any combination chemotherapy has a higher efficacy than a single drug given to the bladder.

Dr. Ashish Kamat:

So, combination chemotherapies are currently available and they’ve been used commonly and they have shown to have robust and in some ways comparable efficacy to BCG. So, I wouldn’t rush to a radical cystectomy, I would say, “well, if you don’t have access to BCG, your physicians should have access to chemotherapy, so go on the chemotherapy route.”

Rick Bangs:

And are there any clinical trials that might be relevant beyond the chemotherapy option?

Dr. Ashish Kamat:

There are clinical trials that are ongoing, but the clinical trials that are currently ongoing and have finished and leading to drug approvals are in the more advanced stages of non-muscle invasive bladder cancer. Because BCG is so effective, but it still is not effective on a hundred percent of patients. Most of the drugs have been focused in that what happens after BCG patient population. So, there’ve been trials that have been completed and have led to the approval of pembrolizumab, which Merck’s makes, for example. There’s FerGene which has made by… As you mentioned the sponsor of this podcast, which has completed its studies and been published, and the data is very exciting. But it hasn’t been approved yet because it hasn’t gone up in front of the FDA for that process.

Dr. Ashish Kamat:

There’s other agents, such as laser Therapy and there’s other antibody drug conjugates, [inaudible 00:20:49] called Genesis many different drugs and agents. And again, in full disclosure, I have been part of a lot of these studies. So, I’m excited about them, but they have not been studied in the upfront setting head to head against BCG. Partly because, number one, it’s difficult to go head to head against such an effective drug and just purely for financial reasons, because you would need a huge study with millions and millions of dollars poured in with uncertain results. Trials have not been designed in that arena.

Dr. Ashish Kamat:

That being said, because it’s been shown that these drugs are now effective in the later stages, there are studies that are looking at these in a head-to-head comparison against BCG. So, for example, a close cousin, as you would say, of pembrolizumab, which is a tislelizumab which is the same body of drugs which is the checkpoint inhibitors, is being looked at head to head against BCG, but in European studies. So we don’t have any drugs that are approved in the earliest stages. And we should be a little careful about rushing into using these more toxic, more intense drugs in an earlier stage until we know that they actually have equivalent if not better efficacy.

Rick Bangs:

So it sounds like there’s a lot of work being done and a lot of options that may already be in motion. Are there additional options, new options that aren’t even in a clinical trial setting at this point and showing any promise on a preliminary basis?

Dr. Ashish Kamat:

Oh. Yes. There are a lot of these as I mentioned are in clinical studies either phase one or two, so that’s pretty early still. But even before that, there’s mechanistic drugs that have been developed just based on the better understanding of the immune mallafry of effects of BCG and the immune response that occurs in the bladder. Like I said, BCG has been around forever. But some of the tools that we have today to understand how BCG works have only been around for the last three, four years.

Dr. Ashish Kamat:

And once you understand exactly how BCG works, you also can get a sense as to how it doesn’t work, or why it doesn’t work. And for example, the STING pathway or the ADC pathway, or just the checkpoint inhibition PD-L1 pathway, all of these have been more intensely and interrogated and a deeper dive down into the mechanistic aspects. And there are molecules that are in development and have been developed combination therapies using for example, checkpoint inhibitors with chemotherapy, checkpoint inhibitors with BCG itself, or recombinant BCG, or essentially introduce a particular gene into the BCG bacteria and have the BCG make cytokines for example. A lot of this work is ongoing right now, and it’s really an exciting time to be an investigator in the field.

Rick Bangs:

Excellent. So, let’s suppose you’re a patient and you are able to get BCG, but you don’t have an adequate response. What would your options be and how might they be different from the options we have talked about?

Dr. Ashish Kamat:

Again, that’s a very broad question, Rick. And one thing I always want to caution people about is, you have to always make sure that you’re going down the right path with the right partner. And because it’s a partnership between the patient, their family, us as physicians, and then our team. And one of the things to keep in mind is not every tumor that recurs after BCG is necessarily a threat to our patient’s lives. So, if a patient is getting BCG for intermediate risk bladder cancer, and those tumors tend to recur or they do recur after BCG, those tumors are more of a nuisance factor and they’re not a threat to a patient’s life. So, so long as the patient is able to continue to have close followup and get monitored, trying different agents and drugs is perfectly reasonable. And I really would not want patients to jump into having their bladder removed in that situation.

Dr. Ashish Kamat:

Now, on the other hand if patients receive BCG for a high risk disease, and some of them are in the high-risk category, which is extremely high risks, such as T1 high-grade with CIS or micro papillary and other tumors. Then if the tumor does not respond to BCG, it’s very important to sit down and consider that in some ways the safest best option for long-term cure is to have the bladder taken out. And that’s why radical cystectomy is still the number one preferred recommendation. That being said, because we now have a better understanding as to the natural history of this disease, trying different agents, so long as the patient and, and us urologists are in close contact and surveillance and monitoring is on closely so that we don’t miss a window when the tumor recurs, before it spreads trying something is very reasonable. And it’s teamwork.

Dr. Ashish Kamat:

It’s just the urologist, the medical oncologist, the patient, their family, because they have to have visits. But if that happens and that is that’s feasible, then I actually recommend that patients try a period of a drug. And the drug could be the approved drug pembrolizumab, or if the patient does not like the toxicity profile of prembrolizumab, trying intravesical chemotherapy with gemcitabine and docetaxel, which is not an approved combination because it’s an old combination, but it’s highly effective. And if Neta version gets approved, that would be again one of the early drugs that I would discuss with the patient saying “Hey, we have this drug that’s very effective, about 25% protection against recurrence in the BCG unresponsive setting, similar to pembrolizumab. Would you like to try this?” And if a patient is willing to try any one of these options, I will be very supportive of him or her trying this.

Dr. Ashish Kamat:

Now, the one thing to keep in mind is that, we don’t want to allow people in a false sense of security in the sense that… Well, let’s just keep trying things until the tumor gets incurable. That’s not what I’m saying. We want to try things till it’s reasonable. And it’s important to remember that we should not let our patients do anything that’s unsafe. And that’s why just going from one drug to another, without recognizing the potential for the tumor to come back can actually kill our patients. That’s a crucial part of this whole counseling, and navigation through the bladder cancer journey that I do with my patients at my center and I know a lot of my colleagues do where they are too.

Rick Bangs:

I think that partnership is so critical as you’re trying to figure out what treatment options to pursue. That is the critical element in the equation. So, thank you so much for your time today, Dr. Kamat I know our listeners would benefit from the information you’ve shared with us and in case people wanted to get in touch with you, could you share your twitter handle or any other information that you would like people to have?

Dr. Ashish Kamat:

Oh. Absolutely. It’s my pleasure to take part in this endeavor and to join you, Rick. My twitter handle is @uroodocash, U-R-O-D-O-C-A-S-H. It’s funny someone asked me why I have that twitter handle and it really was a very long time ago that one of my colleagues just said “Oh. You’re a doc ash.” So, made that twitter handle for me and it stuck. But they’re also welcome to contact BCAN as many patients do. And you, and Stephanie and others in the BCAN team have been very helpful with forwarding some of those questions to me. I’m always happy to answer it in any which way that works for our community.

Rick Bangs:

Thank you so much. So, 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. Thank you for listening and we’ll be back soon with another interesting episode of Bladder Cancer Matters.

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.

 

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