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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and it's a pleasure to welcome to the forum today Gautam Jayram, who is Director of Urology Associates in Nashville, and is well-versed in bladder cancer, especially the nuances of the topic that we're going to touch upon today.

We've talked about the definitions, the endpoints, and the guidance, in another video, and this one piggybacks onto that one. And we're going to discuss BCG unresponsiveness. What does it mean? What does it mean to you, the audience? What does it mean to Dr. Jayram? What does it mean to patients? And how can we better apply the different definitions, and what we have available and what's coming down the pike, to our patients and practice? So, Gautam, welcome.

Gautam Jayram: Thanks, Ashish. Thanks for having me.

Ashish Kamat: So tell me a little bit about how you perceive BCG unresponsiveness when you see a patient in a clinic in front of you. How do you go about determining whether this patient is truly BCG unresponsive or not?

Gautam Jayram: It's a good question, and I think we've gotten a lot of nice formal guidance in a space that was otherwise fairly disorganized years ago, to at least give us some objective metrics on what qualifies as being BCG unresponsive.

So really, I look for recent exposure to BCG, how much exposure they've gotten, and really, what timeframe they've gotten it in. And now again, we have some formal definitions that the FDA has given also that a lot of clinical trial literature has laid out for us. So really, to me, BCG unresponsiveness is the patient who has a high-grade T1 after an induction course. That's probably the highest risk group. But also within that group are patients who have papillary disease, high-grade papillary disease within six months of adequate BCG, and then CIS within 12 months of adequate BCG.

And I can tell you that one of the barriers, roadblocks, Ashish, in the community has been really trying to help doctors understand what constitutes adequate BCG. It's something that is not necessarily intuitive if you're not in this space all the time, but making sure that providers understand that patients need to have six inductions of BCG, and then at least another two of a second cycle, preferably maintenance or induction, to qualify. Because again, there's maybe a tendency for providers to look at just the first induction six and classify patients as being unresponsive, when we know that there is a potential for salvage with another regimen in papillary disease and noninvasive papillary disease in CIS.

So that's kind of how I think about it. But also, from an educational standpoint for us in the community, it's hammering home that point of understanding that patients need to have more than just six of BCG, usually.

Ashish Kamat: I think that's a critical point you made, and you actually packed a lot of information into that. So I'm just going to address a few things. Number one, like you mentioned, it is a definition that we, the GU ASCO group, and the IBCG provided to the FDA purely for the conduct of clinical trials, right? It's not a clinical definition, even though it's made it into clinical jargon. It was never meant to say, okay, let's look at a patient as being BCG unresponsive. It's more about, can we enroll these patients into single-arm studies? And that's what the FDA took into their guidance document and published that in 2018. So that's a great point that you made.

The other point that you made about adequate BCG, again, absolutely correct. Because if a patient just gets induction BCG, you could salvage 67 to 80% of these patients with another course of BCG if they have CIS. And again, this whole reason for adequate BCG is because of the FDA definition, allowing single-arm studies, right? So, great points that you made.

Now, in your experience, obviously, you run a large group practice, but I'm sure you communicate with other folks, how difficult is it to actually get a patient to fall into that category of having had adequate BCG in today's day and age when we have a BCG shortage?

Gautam Jayram: Yeah. I think it's disparate. It differs based on where you are. BCG allotment is predicated on historical use of BCG. And so, for example, in my area, in a fairly large urban area in Nashville, with our group being 35 urologists and having historically one of the biggest footprints in this region, we have not seen terrible effects of the BCG shortage. We do have kind of some month-to-month issues where I'll get notifications saying, "We have X amount of BCG for the remainder of the month, let's be a little bit cautious." But really, we've been fortunate.

However, I can tell you it's been a very interesting couple of years in that I'm getting referrals, and our group is getting referrals, strictly to give BCG because the solo practitioners, two-, three-urologist groups that may be in rural areas or in the periphery, unfortunately, don't have great access to BCG. So it has been evident that there is a trickle-down effect here.

But I would say in contemporary practice, in bigger centers where you have historical usage of BCG, I probably see three to five patients a month who meet that definition. If you want to strictly say carcinoma in situ, that's a smaller number. But I would say those patients definitely exist. But the question is identification. And bigger groups like mine and larger, more sophisticated centers are starting to use navigation tools. We're starting to use analytics tools to try to find these patients. As you know, bladder cancer can potentially be a disease where patients will see you for a cysto or for treatment and you tell them that their bladder looks good, and maybe they don't follow up like they're supposed to; we don't see them again for another year or two years. And so, adequate identification tools for some of these patients, I think, have been a big boon to help identify some of these people who may otherwise have not followed up or may not have gotten prompt attention.

Ashish Kamat: Now, Tam, you have this patient in front of you, and you've determined that he or she is BCG unresponsive. Right? Walk us through how you now counsel that patient on the different options available.

Gautam Jayram: A lot of it depends on the patient first, right? So, every nail doesn't necessarily need a hammer, but age, history of cancer, the timeline the patient has followed, and patient preferences are huge parts of this.

Certainly, their disease is important. If someone has carcinoma in situ only of their bladder, but they have a very small area, focal CIS, potentially, I'm not as inclined to really go up the ladder with my treatments. But I would say overall, radical cystectomy is still kind of the gold standard for BCG unresponsive disease. As you know, it's still sometimes a hard lift to get these patients interested in radical cystectomy, even if you cite the really great oncologic responses to that. So we usually start with alternative treatments to BCG. And in our practice, that usually consists of gemcitabine, docetaxel, doublet therapy, that usually consists of something like pembrolizumab for carcinoma in situ. Now we have adstiladrin, and then we have a very large clinical trials program as well.

So, we have those four or five options. And a lot of it depends on the patient. As you know, some patients are not interested in further intravesical therapy; they're not. They've had a lot of intravesical therapy and they're looking for something else. And then obviously, a lot of patients don't even want to talk about cystectomy. They want to do as much as they can before you talk about that. So, it's really a discussion with the patient. It's taking into account their preferences, how severe their disease is, what their timeline is, what their expectations are in the whole process.

Ashish Kamat: Yeah. No, I think it's very important, right, to keep in mind that even though traditionally, or not traditionally, because BCG unresponsiveness is something that we proposed in 2016, but over the last tenish years, it was meant for patients who are not cystectomy candidates. But for example, in KEYNOTE-057, more than 95% of patients refused a radical cystectomy, right? That's how they enrolled in the study. So most patients are not wanting to have their bladders taken out, even though that's the number one recommendation in both AUA guidelines, NCCN, and EAU guidelines. And what you said about taking the patient's preferences into consideration should obviously be at the forefront of our minds.

With that in mind, do you have certain criteria, again, in a practical way, where you'll say, "Okay, for this patient I might select gem/doce. Now that I have adstiladrin for this patient, I might recommend adstiladrin. Or for IO therapies, right? Pembro is the only one approved right now, but taking a broad cast of IOs or pembro for this patient, let me recommend pembro. Do you have sort of a triage that you do in your mind using patient characteristics?

Gautam Jayram: Yeah. I mean, I'm a little bit biased. I'm a fan of gem/doce. I think it's underutilized, especially in the community. There are certain aspects of giving gem/doce in independent urology practices that make it difficult. There are certain government ordinances that make it somewhat challenging to dispense this in our offices. So as a result, many community urologists don't do this at all. And we have tried to organize a lot of information through LUGPA, and through some of our informational educational initiatives, to help urologists give this. Because in my mind, this is a great tool. It's cheap. And as you know, the data is very comparable, if not superior, to a lot of the newer agents that are out there.

That being said, I think with papillary disease, you have to make sure that it's completely resected, and then certainly gem/doce is an option. The label on adstiladrin is still carcinoma in situ. Although, what we're seeing is that some of my colleagues have gotten this approved from a papillary-only standpoint. But I guess from the letter of the law with how things are being approved right now, I would say gem/doce for papillary disease is probably the easiest thing to do after they're completely resected.

And then for carcinoma in situ, you have adstiladrin and you have pembro. And really, one way to differentiate between those two, it's basically intravesical, versus non-intraves, versus systemic. The one-year data isn't that much different, right? 24, 25% for adstiladrin, 19, 20% for pembro.

Like I said, some patients, I see some patients who just don't want more intravesical therapy. I'm sure you see this too. Patients are tired of catheters; their bladders are beat up. And so I don't think it's unreasonable to offer those patients pembro.

And then certainly, patients who are maybe a little bit older, a little bit more frail, adstiladrin has a really nice dosing schedule. It tends to be easier on unhealthier patients. So I probably err on that for those patients, the older patients.

Ashish Kamat: Yeah. Like I said, personalizing it to the patient. Patients who can't travel, for example, having to ask a relative to bring them once every three months is so much easier. And if a patient has a bladder that's getting close to causing them misery, sometimes they want the bladder out, but they clearly don't want more medication within the bladder, right?

Again, we could talk about this for a long time. We're coming up on time. So let me ask you some pearls that you can share with those that are listening and saying, "Hey, I'd like to do gem/doce in my practice, but for all the reasons you mentioned, I can't." So any pearls for them to take home?

Gautam Jayram: I would say the easiest thing to do is partner with your local hospital center or your local infusion center. Write up a protocol, and hand it to them and say, "Here's how we want it done." And as you know, you can use Michael O'Donnell's protocol from his initial studies, and that's what we did. And we've tried to spread this out throughout large groups across the country to help them.

There is some help on the way, in terms of being able to do this in-house. There is now more guidance on what exactly we need: a negative pressure ventilation system in a hood. A biological safety cabinet is kind of something that is being termed now to be able to mix this and give this. So, probably within the next, we'll have a little bit more clarity on this soon. But I would really, and I think that a lot of us as bladder cancer doctors who do a lot of cystectomies, work with these hospitals, we work around infusion centers that give neoadjuvant chemotherapy. So, it's really not that much of a lift or a stretch to go to them and say, "Hey, here's this thing that is really good for our patients. Can we operationalize this somehow?" So that's the thing that we have done the most.

And then the other thing I would say, Ashish, to a lot of bladder cancer doctors in the space is to consider bringing clinical trials into your practice or finding a way to offer clinical trials. As you know, there's just so much out there right now for patients in this space. They don't want a radical cystectomy. And these trials are really exciting. There are a lot of things today that are going to be really what we use tomorrow. And so, we've had a lot of success basically on that platform, that if you don't want a radical cystectomy. And our trials program started years ago before we had gem/doce, really, and some of these other agents. So, that's all we had, was a clinical trial or a cystectomy. And so, I'm a big fan of clinical trials in the space, and we've had a lot of good results with really prolonging, pushing this disease down the road so that patients can keep their bladders.

Ashish Kamat: It's been a wonderful evolution. We used to, like you said, have nothing other than radical cystectomy or trying single-agent chemo. Now we have two approved drugs, which sort of set the bar. We have to give them credit. They're not phenomenal results, but they kind of set at least a lower bar. And then newer agents that seem like they're surpassing that bar. And of course, now we have gem/doce, so our patients have options. And I really appreciate you taking the time and spending it with us here on UroToday and with our audience. This was great. Thank you, Tam. Thank you a lot.

Gautam Jayram: Thanks so much.