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Alicia Morgans: Hi. I'm talking today with Dr. Josh Meeks of the Northwestern University Feinberg School of Medicine. Thanks so much for talking with me today.

Josh Meeks: Thanks, Alicia. 

Alicia Morgans: So the BCG shortage, and non-muscle invasive bladder cancer in general is a really big problem, actually, in the US right now. I'd love to hear your take on the BCG shortage itself, what that's really resulting in in your day-to-day management of these patients.

Josh Meeks: So the BCG shortage is real. It certainly is starting to impact many of our patients across the US. It seems to be very dependent on where you are though. So as we heard this was coming down the line, I think a lot of places, based on what happened around five years ago, started stocking up on BCG. For example, we have plenty of BCG at our hospital, but among other hospitals within our system, I know there's a shortage.

So the real question is, what do you do within a BCG-rationed era, and how do you manage patients, and how do you select? And I think there's some general principles we try and keep in mind. So probably the most important is induction. So the first six doses in patients that are certainly high-risk ... And so high-risk non-muscle invasive bladder cancer would be all the T1's, carcinoma in situ, and in general for the AUA Risk System, the high-risk would be greater than three centimeters. So even the high-risk but lower than three centimeters, all those are considered intermediate risk, there's an option in our guidelines that can consider intravesical chemotherapy. So doing something like gemcitabine for induction, and then maintenance at 3, 6, and 12, that may be sufficient for a number of folks. 

So once again, just trying to prioritize people who come in with new onset non-muscle invasive disease that are high-risk to get the BCG. Additionally, people who are on maintenance ... And for people who are high-risk, we try to give them three years of maintenance, because nearly all studies that look at maintenance BCG tends to show a benefit in recurrence if you get maintenance BCG. Those folks, after a year, if you don't have it, then I think it makes less sense to give it to people on maintenance as opposed to people who are coming in. Or the other option many people are doing is cutting it to third dose.

So I think the general principle that this tells us though, is that having a single supply of BCG, where it's all coming from one source, is probably not enough. And that's one of the concepts behind the 1602 SWOG study. Giving Tokyo-172 for patients to see if there's potential to get another source of BCG that's as effective, and potentially open the road to have that supply available in the US.

Now I think that for people on trial it's an even bigger concern, because there's a number of trials now for patients both BCG-naïve as well as BCG-unresponsive where they're getting BCG plus, for example, a checkpoint inhibitor. And so it's kind of a question of will we have enough BCG for them, but I think coming to that strategy of how you're going to manage those patients, every practice is having to deal with it. As a community, as urologists for sure, we're trying to figure out which places have it and how to get patients to those places.

Alicia Morgans: So call tell us a little bit more about the Tokyo strain? Is it different? Is it as effective? Or I guess we're studying it, but can you tell me a little bit more about that, and what your hope is for that strain?

Josh Meeks: Well so the trial, it's a three-arm trial. It's comparing TICE from Merck, to Tokyo-172, to Tokyo-172 plus priming. So patients get a prime 21 days prior. And so you're right, it's a different subtype of BCG. We know it's very effective in Asia. Compare it head-to-head, it appears to be a little more effective than the Connaught strain, for example. But we've never compared it head-to-head to TICE, for example, in the US. So it'll be very interesting to see how that looks. 

It may be that, and I would guess at our response, patients are very different based on their genetic makeup. That's one of the questions. You think about what determines response to BCG. There's several things. One is the surgeon, and how good of a job they do. Ideally, you've removed everything. But we know that how we treat these tumors, blue light, not blue light, can be very different between institutions. Second is how the tumor itself behaves. So there is some definite intrinsic tumor biology that predisposes them to recurrence. And the third is an immune response to the BCG. And so we know that people with Th1 or Th2 response, the amount of adaptive and innate immunity they can develop, very different for patients. So, that plays a huge role. And then the fourth would be the BCG itself. The amount of colony-forming units, and the strain. 

So all those factors come together. It's an incredibly interesting therapy. We've had it 40 years. It's been effective, so we know very little about why it works, because there's very little motivation to change it if it's so effective in everyone. But I think about like a shotgun, in that it kind of has a good blast effect, but at the same time it's not very precise. And when people fail, we have to come up with better therapies for them. 

Alicia Morgans: Absolutely. So not only are we dealing though with shortages, BCG doesn't always work, even for non-muscle invasive disease. Can you tell us a little bit about the strategies that are being developed, the studies that are being done to address that unmet need?

Josh Meeks: I think there's two broad types of therapy. One is more a very systemic-therapy based, driven-by-checkpoint-based therapy. There's a number of those trials that are already out there. Monotherapy. The earliest one that we've seen is KEYNOTE-57. That's pembrolizumab, reported at ESMO. And honestly, the three-months response rate is only at 38%. I think a lot of us anticipated that it would be a much higher response rate. A lot of anticipation going into that trial. 

Now the benefit of checkpoints, obviously, is that 38% may continue on for a year. So if you get to a year with a 38% response rate, that would be sizeable. But I think you have to compare that to something like gemcitabine/docetaxel, which we've been given sort of off-label, all based on Mike O'Donnell's work from Iowa. Which overall, that data is very strong as well, and as good without the potential systemic toxicity.

So I'd say one arm of it is systemic therapy. And that may be best for patients with very high-risk disease. So T1 gets BCG, has a T1 recurrence, can't get a cystectomy. They're considered if you have a T1 recurrence that fast, it's BCG-unresponsive. But those are high-risk patients for progression in advanced disease metastasis. Very different than someone who just has a CIS recurrence. 

And so many of those therapies, I think we still have other options that are intravesical therapy. Something like Instiladrin is an option, and we're waiting to hear the Phase 3 data of that. There's a number of viral therapies targeting the bladder that would still put that in hands of urologists. It could be in two to three years, we have a number of options in the landscape of BCG-unresponsive disease, and you're picking second-line therapy, third-line therapy, like many do for advanced-stage disease.

Alicia Morgans: True.  Well, it's fantastic that we have these options coming down the pike. Not so fantastic that we have these upcoming shortages expected. But I really appreciate you taking the time to talk through these issues with us. The really burning issues in non-muscle invasive disease. And I appreciate your time.

Josh Meeks: Thanks, Alicia. It's my pleasure.

Alicia Morgans: Thanks.