BCG Shortage: What’s on the Horizon to Replace? - Joshua Meeks

February 28, 2024

Zach Klaassen and Joshua Meeks discuss the ongoing BCG shortage impacting bladder cancer treatment, tracing its origins back to production issues in 2012 and guideline changes in 2016 that increased BCG demand. They highlight the shift towards using Gemcitabine-Docetaxel (Gem/Doce) as both a salvage and primary treatment for high-risk bladder cancer due to its effectiveness and availability. The discussion also covers the BRIDGE trial, a pivotal study assessing Gem/Doce's efficacy, and several large trials investigating checkpoint inhibitors as potential BCG alternatives. These include AstraZeneca, Merck, and Pfizer trials, each exploring BCG plus induction maintenance with a checkpoint inhibitor. Dr. Meeks emphasizes the significance of upcoming results for these trials and the SunRISe-3 trial, which examines the effectiveness of sustained release therapy TAR-200 with and without Cetrelimab.


Joshua J. Meeks, MD, PhD, Urologic Oncologist, Associate Professor of Urology, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Jesse Brown VA Medical Center in Chicago, Chicago, IL

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA

Read the Full Video Transcript

Zach Klaassen: Hi, my name is Dr. Zach Klaassen, and I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And we're here in San Francisco at GU-ASCO 2024. Delighted to be joined by Dr. Joshua Meeks, a urologic oncologist at Northwestern University. Thanks so much for joining us today.

Joshua Meeks: Thanks for having me, Zach.

Zach Klaassen: So we're going to talk today about a presentation that you gave, discussing basically what we do when we don't have BCG, and what's on the horizon. So just to sort of take us through where we are and how we got here, what's a timeline from the BCG story, from a historical perspective?

Joshua Meeks: Yeah, I think it's a critical time for this. We probably started in the 2012-ish, where Sanofi Pasteur had issues with production. And then I would say, it was really not appreciated that we kind of caused some of the problem ourselves when our 2016 guideline came out. And if you remember, at that time, a lot of people treated bladder cancer like ADT, right?

Zach Klaassen: Yeah.

Joshua Meeks: You have a tumor, you get some induction, you get six doses, and then you just do surveillance. And if another tumor comes back, you get more BCG. But in that guideline, we said, okay, we have data now that you need to do induction and maintenance for high-risk patients, and that ends up being a lot of BCG. So that affected our supply. So that's an inclination in 2016, and then all of a sudden Sanofi just says, "No, they're done." And then Merck became the only supplier.

And right now the estimates are somewhere between 600 and 800,000 vials that are created. I don't think we know the true scope of the problem of how many people are affected, that denominator. I've heard anywhere from 30 to 50% of patients just don't have BCG. And so there's a lot of things there. And so again, we've had a shortage at Northwestern for a very short amount of time, but we've been rationing, so we give a third dose, we give a half dose, we coordinate patients. But I'll tell you, people across the street, and the distribution part of it is huge. So if you somehow don't get distribution, then you just don't have access to it.

And so then I think, for me, it shapes the whole thing as far as patients diagnosed with high-risk bladder cancer, and you're talking to them, and they're like, "Okay, we've heard of this, what is it, BC..." And you're like, "Yeah, it's BCG, it's tuberculosis, it's the vaccine. It's been around since the turn of the century." And they're like, "Okay, when do we start?" You're like, "Well, listen. So we're going to start, we're going to give you ideally 15 doses, but a lot of it depends on the supply. And then it's going to be third or half doses." "Well, is it as strong?"

And I would say that in general, the community of us as urologists has responded to that. I really haven't seen people who are doing worse by having split doses. And alternatively, as far as what's on the horizon, gemcitabine-docetaxel, the dual chemotherapy regimen developed really at the University of Iowa for salvage, actually works really well in the BCG-naive setting. So I'm not seeing people who are coming who got Gem/Doce who had failures. They seem to do well. And that's being addressed with the BRIDGE trial, so Max Kates's randomized trial. It's a non-inferiority trial. I think that's on the very near horizon for FDA approval for competing. Now, you could say that even if it's successful, if it's non-inferior, right now it's what people are using.

Zach Klaassen: It's what we're using. Yeah.

Joshua Meeks: So in some ways, it has won, but I think we need that data to be able to reassure our patients. I think the strain data is really interesting. So Rob Svatek's trial, S1602, that trial is a thousand patients; Tokyo-172 in two-thirds of the arms. And so the first comparison is TICE versus Tokyo-172. That's non-inferiority. And then the second part of that is Tokyo-172 versus Tokyo-172 primed. So that's a really big question, and it's a superiority trial to see if you can, for example, take patients who may not have responded and get a better response. So that's another set of strain data. And again, that data's complete, right? December 2023, all of that was collected. We're hoping to get those results in 2024. And so that's exciting.

And then I'd say, from another strain perspective, the Dana strains coming in, and it's being used in SunRISe-3, so that's Janssen's trial. And that's really remarkable because the problem many people have had is, how do you beat BCG if you can't compare yourself to that? There's no supply. So how do you compare yourself to that? And so Janssen said, "Okay, we're going to bring in the data supply. Two to three years cohort B is going to give that. So over 300 patients are going to get that." So we'll see how it does in the US. I mean, I don't think the goal of that trial is to bring that strain in and get it approved, but it'll be really interesting to see how that strain does.

Zach Klaassen: It's interesting because you made a good point. If we don't have BCG, how do we run trials against it? And in my center, we have not had BCG for more than two years. So we're on, I guess, the other end of the spectrum, where we've had to go with it. And to your point, let's get a little more into the Gem/Doce. We've used Gem/Doce first when BCG failure, and then now we just use it as primary. And to be honest, it works well, and we're in the process of also looking at our data. But you mentioned the Iowa data and certainly, the BRIDGE trial is going to be fantastic. In your situation, for the listeners out there, if they don't have BCG, Gem/Doce's available, just sort of go through how that's given and what that process entails.

Joshua Meeks: So I think there are a lot of benefits to Gem/Doce. So number one, at most academic places, it's going to be available from your pharmacy. So giving it is going to be straightforward. And we have no problems with that. The problem is that it's a little bit more time. So it's usually an hour and a half in the office. They get the Gem, and then you empty the catheter and put the Docetaxel in, and pull it, and they leave. So I'd say that in general, it's straightforward, but they are there longer.

I'd say that the other part of it is that people can get it when they're immunosuppressed. So that's a huge benefit. Now, on the other side of things, a lot of the LUGPA practices don't have access.

Zach Klaassen: It's hard, yeah.

Joshua Meeks: So it's not perfect for everybody. But I think your options if you have a high-risk patient are, you give BCG, you give Gem/Doce, you do a trial, you refer them to a different institution. Sometimes you have to consider cystectomy.

Zach Klaassen: Sure. Yeah, absolutely. Let's talk about some of the trials that you're excited about. I know you spent a good portion of your talk on some of these trials. So just roll through some of the ones that are on the horizon that you're really looking at.

Joshua Meeks: Well, there are three 1000-patient trials that are all with checkpoint, right? So AstraZeneca has one, Merck has one, Pfizer has one. They're all there. They all contain BCG as a standard of care. And then there's BCG plus induction maintenance, plus a checkpoint, versus usually induction. And then you get rid of that and the checkpoint is maintenance. So all three of those are done. They're all closed.

Zach Klaassen: That's great.

Joshua Meeks: And we can't wait to see, can you, number one, replace maintenance with a checkpoint, or is there a bump to adding a checkpoint? And there may be, we know of those high-risk patients. If you take care of enough bladder cancer patients, you're going to have progression. And unfortunately, people are going to die from bladder cancer, even non-muscle invasive disease. So will you rescue those? But alternatively, what are you going to do with toxicity?

Zach Klaassen: Sure.

Joshua Meeks: Because a medical oncologist that sees a patient for metastatic disease that gets 5% toxicity, that's part of the label, part of the expectation. But our patients who come in that get BCG, they're not expecting that.

Zach Klaassen: That's right.

Joshua Meeks: So it'll be interesting to see, number one, is it effective? Is it superior? Number two, how do patients tolerate the toxicity? And how is that going to be indicative of use? I think those three trials are super exciting.

I think the other big one is SunRISe-3. So SunRISe-3, a thousand-patient trial. Again, this is Janssen's trial of, it's TAR-200 plus Cetrelimab, that's cohort A. Then cohort B is the Danish strain, and then the third cohort is just TAR-200 alone. So I think it's nice you've separated the components. You'll see how TAR-200 does in that setting. And as urologists, we love the thought of that, right? You're going to have sustained release, it's something that we can put in, tolerability very good. So I think we're really excited about that. Again, going head-to-head, but to do that, you had to maneuver around and bring the BCG in.

Zach Klaassen: I mean, if you look at where we are early 2024, we could be sitting here having a discussion in the next 12 to 18 months, and we could have a ton of data to discuss. And hopefully, we do, because when we look at not just the BCG availability, but also what do we do for the patients in BCG-unresponsive. And so I think this disease space is about to explode over the next year or so.

Joshua Meeks: Yeah, I think folks are going to have to figure out much more discussions with patients about not just how do I treat you, but what's the best choice for you? And some of that's going to be function, it's going to be bladder capacity and what they can tolerate. Some of it's going to be distance, how often they can come in and see us. So that's a great discussion to be able to have. We're going to have choices, we're going to have to be thoughtful. You would love for there to be some science behind it.

Zach Klaassen: Absolutely.

Joshua Meeks: A little more of an inflamed bladder, maybe they don't need more BCG, maybe there's something else. So again, those are all opportunities I think we're going to have in bladder cancer.

Zach Klaassen: And I think too, you made a point about not every center's going to have everything. I think that's going to be logistically, we'll have to sort maneuver that. And even every academic center's not going to have everything. So I think how we not only get the information out to our colleagues that maybe aren't academics, but how we partner with them in getting patients to the right place is going to be important too.

Joshua Meeks: Yeah. So exciting time for bladder cancer.

Zach Klaassen: That's great. Awesome discussion. Anything we haven't touched on, any take-home points for our listeners that you'd like to make?

Joshua Meeks: Yeah, again, I think the next phase of this, I really think, and I'm always going to put a plug in for some of the science. I'm trying to figure out, we treat this as one-size-fits-all. I think that's going to work if you've got a sledgehammer that's incredibly effective, but I think as we learn more about the science behind these tumors, maybe that allows us to figure out ways to better treat them. So again, scientists are working on that, everyone's working on that. So I'm hopeful down the road that that's something that we'll be able to provide.

Zach Klaassen: Absolutely. Josh, thanks so much for your time during a busy meeting, and for your expertise today.

Joshua Meeks: Thanks, Zach.

Zach Klaassen: Thanks.