Patrick Hensley: Thank you.
Frances Martin: Thank you for the invitation. Well, thank you so much for letting us present our paper where we talk about the contemporary challenges in the BCG-unresponsive non-muscle-invasive bladder cancer patients. Our talk today outlines the paper that we presented, which talks about the strict definition of BCG-unresponsive disease. The challenges that limit us with using this strict definition, especially in the era of BCG shortage, and how can we use other concepts such as BCG exposed and BCG intolerant to help us treat patients. And Dr. Hensley's very familiar with the challenges of the CIS-only study design, and can take us through some of the papillary-only diseases.
And we also want to stress some of the pathways for patients who are considered BCG-exposed to be able to get newer novel therapies. The strict definition of BCG-unresponsive non-muscle-invasive disease was originally designed so that we could categorize patients for study design, so that there would not be a broad variability within patients when we were trying to look at different treatment options after BCG. But it's limited to persistent or recurrent carcinoma in situ with or without papillary disease within 12 months of completing BCG, recurrent high-grade papillary disease within six months, or high-grade T1 disease at the first evaluation after the BCG. The definition of this is predicated on the definition of adequate BCG, which we know that it's defined as receiving at least five of the six induction courses plus at least two of the additional doses of either a second induction or maintenance.
We know that despite the idea of adequate induction, only 37% of patients actually receive adequate BCG therapy. So, there's a large population of patients who do not meet that strict criteria definition who have had recurrence, but have been exposed to BCG. So, Peter Black and the team introduced a concept for BCG exposed, instead of the strict BCG-unresponsive definition. In order to allow access to novel drugs for BCG-unresponsive disease, we know that in order to call someone BCG unresponsive we have to have BCG available. Given the shortages that have happened, we have had patients who have never made it to say the maintenance or a second induction course. And so we're hoping that these BCG-exposed patients can be incorporated into ongoing clinical trials, which will expand their access to novel therapies. So, regarding BCG availability, we knew there was going to be a shortage starting in 2012, and Merck tried to rise the occasion. They have committed $650 million for their new facilities.
Their website still proposes that they will be up and functioning by the end of 2026. So we have approximately one more year before they will be in production. We know BCG takes at least three months to manufacture and be available. So, if patients don't have access to BCG and they've been BCG exposed, what are their options? We also have complications currently around papillary-only disease. Most of the novel therapies use single-arm registration trials. And based on FDA recommendations, only use CIS in the evaluable cohorts. There are some other studies that Dr. Hensley will present later this year in the papillary-only disease state, but the CIS only does currently limit our treatment options to either appeal to insurers for allowing us near label use, or compassionate use for these patients. So, there are some techniques that we've talked about to help manage the BCG shortage, which there have been studies that show split dose is adequate, either half dose or third dose. And despite the lower dose, it is still recommended that we keep the schedule the same, or the exposure to the patients the same, with six inductions and three maintenance, to see that they have gotten an adequate immune stimulation.
We recommend reserving BCG for high-risk patients, and not low-risk patients. And make sure that patients actually get the five plus two regimen, so that if they are unresponsive, they can then be classified for logistical reasons to receive additional therapies. So, in summary, during this shortage, we need to come up with compassionate uses of novel therapies for patients that may not meet the strict definition of BCG-unresponsive, and we need to weigh clinical benefits for the access limitations and regulatory burdens of these novel therapies. So, institutions are encouraged to develop clear triage policies, which patients are going to get BCG. They should explore clinical trials for these BCG-naive or BCG-exposed patients, and work with manufacturers, so that we can get early access for these patients. So I know Dr. Hensley has some ideas about how we can manage some of these novel therapies.
Sam Chang: Yeah. Patrick, why don't we start off with that?
Patrick Hensley: So, I think there's two big challenges that are facing us in routine clinical practice outside of the clinical trial world right now. First is we all, because of BCG shortage, have a big swath of patients who in the treatment-naive setting are treated with first-line gem-doce, and we don't really have a great option after gem-doce failure, because those patients don't meet BCG-unresponsive criteria, so they don't have access to novel intravesical therapies. I think Dr. Martin did a great job outlining appropriate use of compassionate use. And I have a couple patients in my practice that went straight from, for instance, gem-doce to Adstiladrin. And you just document in your note that this patient really prefers to continue with bladder preservation strategies, and we really don't have access to BCG to get them to that BCG-unresponsive state.
So, what do we do with the gem-doce unresponsive cohorts? And then, like Dr. Martin mentioned, I think BCG-unresponsive papillary-only disease is a really challenging cohort, for sure. We've seen NCCN category 2B support for some of the, particularly at Adstiladrin and Keytruda in the BCG-unresponsive setting for papillary-only disease. And for the most part at our institution we've had good luck getting insurance coverage in that setting. But the FDA has made it very clear that they're going to expect prospective randomized trials in the papillary-only disease setting. So, we're really in a messy spot in terms of this BCG-unresponsive state, especially considering the shortage.
Sam Chang: Yeah. I think you raised two, or multiple good points. I mean, just pearls coming out of your mouth every time, Patrick, which I always appreciate, is first, there are going to be, and there's a category of patients, and that's why I really appreciate the BCG-exposed, there are many, many patients that never get to the points that Dr. Martin raised regarding the five plus two, never get to that point. So they don't qualify for trials. We don't really know in essence what the next best step is. And then this morass of patients that might've gotten one dose of BCG. Okay, they're kind of BCG-exposed, but then got monotherapy with gemcitabine. Or they might've gotten combination therapy. So, a couple questions that I have is, for those patients that get, say, single-agent monotherapy with gemcitabine do once a week for six weeks, and they still have tumor, or when do you consider a patient that is chemotherapy unresponsive? Do you do two cycles? Do you do three six-week cycles? When do you determine that they're not responding to therapy?
Frances Martin: I think we follow the same algorithm as we do with BCG. Whether that's the correct policy is obviously there's no data to prove that, but I do think we generally would recommend the induction course. And if they fail single agent, we would consider an induction course of dual agent. But there's obviously we have not done any sequential studies in this patient population to know what is the next best step for these.
Sam Chang: No, I think that's exactly why I'm nodding my head, is that's exactly what we do exactly based upon the data that's non-existent. But we have anecdotal data. But they're clearly patients just as we've seen with immunotherapy makes more sense raising. But it also makes more sense if you are exposing the tumors to more chemotherapy over a period of time. There are going to be patients that respond and patients who don't. And so we have definitely introduced more of the combination chemotherapy, but it is logistically difficult, and there are a lot of practices who don't. And clearly, gemcitabine monotherapy has some benefit and some responsiveness.
So, I love actually the algorithm you said of, okay, we do monotherapy, we do six weeks, there may be a small tumor burden, or there seems to be some benefit, but maybe we do then a second round of combination. I'd love that in terms of a second induction course. Tell me as you all, because this is a question that we get raised a lot, is we don't have BCG. How can we get more BCG? Tell me any of the strategies that you all have in terms of trying to get more BCG. Actually, we turn to our pharmacy to basically go to our distributors and say, "Look, we're running very low. We don't have what's going on." And their response is oftentimes, it falls on deaf ears, but tell me if you all have any strategies regarding trying to solicit and get more BCG.
Patrick Hensley: I think that's exactly right. You have to be advocates for your practice, advocates for your patients. The pharmacists and distributors don't have a grasp on the gravity of the BCG shortage. To them, that's just another drug that's in scarce supply. But we're talking about bladder preservation here. We did, just like you did, I mean, we were fortunate enough to get some stakeholders from our institutional pharmacy leadership, our distributors and Merck all together on the same call. And we just laid out the struggle and the shortage. And all of them were actually pretty surprised to hear how much it was impacting our practice, and it alleviated a lot of the shortage. They were able to redistribute some of their allocated supply to our institution, and it helped.
The other things like Dr. Martin outlined, we're being very judicious with our BCG. Only high-grade patients receive BCG. We are commonly doing third-dose split-dose BCG. There's some retrospective and anecdotal evidence that suggests that it's just as efficacious. But you really just have to continue to be advocates for your patients. And the other thing that we've done is I'm not below calling community practices and trying to get patients in with other providers who may have it. You'd be surprised that some of the lower-volume bladder cancer community practices have stockpiles of BCG, and bouncing patients either back to their referring provider, or to a new community provider is something that we've done frequently.
Sam Chang: Excellent points again. The inconsistency of that supply chain is somewhat difficult to comprehend when some of the busiest centers, some of the largest cities have a dearth of BCG where surplus exists in a city of 25,000. I still struggle with it, honestly, just as you have. And I think a really good point that I will pass on to the large group practices is just setting up that communication, just as you did, of bringing in the stakeholders of saying, "Look, we're a large practice. We've done this. We've engaged in trials. Whatever you all can do to help." And to Merck's credit, the building of the second facility, the goal of tripling production, as that ramps up I think really will help things quite a bit, because we have a lot of exciting treatment options in the BCG that's being studied and even being presented.
But as we go over time, we understand the backbone of BCG therapy, it is a therapeutic success. And we have talked about all the side effects with BCG, but a lot of people have gotten BCG successfully, and hopefully that'll be able to continue as we get better access. So, Dr. Martin and Dr. Hensley, I want to thank you both for spending some time with this. And we look forward to hearing from both of you all again regarding other strategies that you all have taken in place, other things that you've integrated in your practice, because I'm great admirers of both of you. So thanks again.
Patrick Hensley: Thanks, Sam.
Frances Martin: Thank you.