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Zachary Klaassen: Hi. My name is Zachary Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today on UROToday by Doctor Cheryl Lee, who is a urologic oncologist and Chair at the Ohio State University department of urology. Today, we're going to be discussing AUA South Central section presentation from Dr. Lee, the top 10 reasons why BCG as a monotherapy will cease to exist. Dr. Lee, thanks so much for joining us today.

Cheryl Lee: Thank you so much, Dr. Klaassen. It's so wonderful to be here and to be here with the entire team from UroToday. I really want to just thank UroToday for talking about an important topic of interest for urology, which relates to the use of intravesical BCG. And at the South Central section meeting, I presented just my thoughts on the top 10 reasons why intravesical BCG as a monotherapy will cease to exist in the not so distant future.

Number 10, we all know that there's some challenges of administration of BCG. Many patients experience side effects, irritative voiding, some systemic effects. In fact, 5% of patients become intolerant to the therapy and need to discontinue their BCG. We also know that patients have challenges with dwell time. And for those with low bladder capacity, neurogenic bladder, or other challenges, it can be difficult to actually deliver the therapy. And of course, for those with high-risk nonmuscle-invasive disease, the treatment intensity of three years of maintenance can be daunting. So ultimately, patients are happy to try something else.

Number 9, let's face it, BCG will even face increased competition in the setting of intermediate-risk nonmuscle-invasive disease. A great example of this is the UGN-102 ENVISION trial. In this phase III study of 240 patients with low-grade, intermediate-risk, nonmuscle-invasive disease, patients were treated weekly with a chemo-ablative therapy that uses mitomycin within its thermal gel.

And in this nonsurgical chemo-ablative strategy, patients actually had a complete response rate at three months of almost 80%. And in fact, those responses were pretty durable. So if you achieved a response rate at three months, 80% actually maintained that response at 12 months. So BCG will be facing competition in that space as well.

Number 8, a targeted agent will drive precision care, and BCG is not a targeted agent. A great example of a targeted agent under study is erdafitinib. And in the THOR 2 study, erdafitinib was investigated in the population of patients with BCG unresponsive disease that actually had FGFR alterations or fusions. And those patients were randomized as compared to patients being treated with intravesical chemotherapy, and that was with either intravesical mitomycin C or gemcitabine.

Now, the study did not accrue its intended number. But even in the 73 patients who were in that cohort arm, we could readily see that those who received erdafitinib had better recurrence-free survival than those who had chemotherapy. And in fact, the median recurrence-free survival was almost 12 months in the chemotherapy arm and had not been reached in the erdafitinib arm. So I think we can see that we want to strive towards agents that are targeted. We want precision care for patients with nonmuscle-invasive disease, and BCG just can't provide that.

Number 7, novel agents are improving drug delivery over BCG. And again, a great example in the setting of BCG unresponsive disease is the SunRISe-1 study. Now, this study looks at the TAR-200 investigational and targeted releasing system that was designed to actually provide extended local release of gemcitabine into the bladder. It's delivered and introduced by cystoscopy quite easily, and it has this pretzel-shaped appearance, and thus is nicknamed “the pretzel.”

In the SunRISe-1 study, TAR-200 was explored in the context of BCG unresponsive disease. Now, there were a number of other cohorts in that trial, but the one that really actually showed a difference here and had enough patients to be evaluated was in this cohort 2. And its population of 80 patients. You could see that those who had the TAR-200 device implanted had a complete response rate at three months of almost 80%.

So if you think about the ability to achieve that complete response rate in a fashion that is less invasive for patients, with the introduction of one pretzel every three weeks, you can imagine that that would be much more attractive to patients rather than their weekly BCG introduced via Foley catheter. Importantly, the TAR-200 device is tolerated well with low toxicity.

Number 6, novel agents have more convenient treatment schedules than BCG. I mentioned that the TAR-200 was delivered every three weeks, but we could look at nadofaragene firadenovec, or Adstiladrin, and really see that treatments can be delivered even in a much more relaxed fashion, much more desirable for patients. And we know that in this trial, using nadofaragene firadenovec in the context of BCG unresponsive disease, we were able to see response rates in patients with carcinoma in situ of up to 24% at a year.

Impressively, this group recently presented their five-year data. And although the number of patients with carcinoma in situ at 57 months follow-up are only about 6% that are recurrence-free, we can see that the five-year cystectomy-free survival rates are actually pretty impressive at over 40% in that patient group with carcinoma in situ. So I show this to say that there are promising agents in the context of BCG unresponsive disease that are delivered in schedules that are more advantageous for patients. This agent is delivered every three months for five treatments. That's much easier than our regular induction course with really up to three years of maintenance therapy.

Number 5, novel agents are synergistic with BCG. Now, this is being explored initially and was reported in the BCG unresponsive setting, but we know that many other agents are starting to be explored even earlier. But I think we can look at a great example in the QUILT III study, where we see a combination of intravesical BCG and ALT-803 or Anktiva.

When these agents are utilized together in combination in the context of BCG unresponsive disease, we see that there are some pretty impressive complete response rates, over 70% in cohort A, but the duration of response is also impressive with over 60% duration of a complete response at 12 months. So when we think about BCG as a monotherapy, we have to recognize that it has several limitations that we've been talking about. But now we may think more about BCG in combination with other agents to provide very favorable results and durable results.

Number 4, and I think we all know how important this is, the BCG shortage happening worldwide. In 2012, Merck became the sole manufacturer of TICE BCG. Now, they did commit to build a new production facility that's due to open, and this is a picture of it here in Durham, North Carolina. But in the interim, many urologists have had limited access to BCG, which means patients have lost access. And we definitely know that despite the recommendations from the AUA, the SUO, the AACU, BCAN, and LUGPA giving us some guidance on how to be most efficient with our BCG, there's still a lot of nonstandard dosing going on, and so patients are losing.

So this is a very important factor and driver for us to think about novel agents not only in the BCG unresponsive setting, but in the setting of BCG-naive disease. And that brings me to number 3, where chemotherapy is challenging BCG as a frontline agent for high-risk nonmuscle-invasive disease. And the best example of this is the BRIDGE trial that's currently accruing in ECOG.

And in this trial, patients with high-risk nonmuscle-invasive disease are being randomized to gemcitabine and docetaxel, both delivered intravenously, versus BCG. The primary objective is event-free survival, and that includes negative events such as cystectomy. So I think we really have to consider the fact that we've used some agents off label, but now they're being studied in the context of BCG-naive patients. So this is, I think, very important.

And last, I'll talk a little bit about this concept, again, of combination therapy with BCG. We know that the combination of BCG with PD-1 or PD-L1 inhibitors may present an approach to actually boost anti-tumor immune responses, and that may yield better antitumor activity compared with either agent alone. And we've seen this with immunotherapy in the context of metastatic disease, with these drugs being paired with antibody-drug conjugates, with chemotherapy, and with other agents.

So we're seeing it also, as we in the nonmuscle-invasive disease space with oncolytic immunotherapy like Credo being paired with pembrolizumab in combination to actually result in pretty favorable results in the context of BCG unresponsive disease. So we're seeing now multiple phase III studies of PD-L1 and PD-1 inhibitors in the context of BCG-naive disease being studied in these patients with high-risk nonmuscle-invasive disease.

And there are several studies, large studies, that are ongoing. And they're randomizing patients not only to look at drug efficacy, but also to look at the intensity of therapy. I'm going to say that's number two. And number one, of course, to try to have a better outcome for patients. So I would say this combination therapy is probably the biggest threat to BCG as a monotherapy. We may see that in combination with some of these immunotherapy agents such as sasanlimab, which is actually a subcutaneous immunotherapy that may allow us to diminish the burden of treatment of BCG.

Zachary Klaassen: Dr. Lee, thanks so much for a great presentation. This was one of the best presentations at the South Central meeting, and so I’m grateful you're sharing it with our UroToday listeners as well. You have 10 phenomenal reasons why BCG as monotherapy may cease to exist. Are there two, maybe three that you think are maybe a little more important than the other ones? It’s kind of like choosing your favorite child, it may be difficult. But are there a couple that you're particularly passionate about or think are important?

Cheryl Lee: Yeah. I mean, one, I would say the BCG shortage. That really has hit a lot of urology practices hard. And I would say, even though several of the larger centers, and particularly academic centers, do have greater inventory, even some of those institutions have limited access. And like we know, necessity is the mother of invention. So it's a reason for us to really think outside of BCG as a limited single-agent therapy.

When I think about the advances in bladder cancer across the spectrum of the disease, as we see these novel agents, we know that the best treatment strategies are not monotherapies. We know that for muscle-invasive disease, we know that for metastatic disease. And we know that a lot of these novel agents in combination may have improved efficacy, and that's what I would say is the other probably one of the greatest reasons why I think we will be looking at BCG differently. Will it completely go away? Probably not.

But I would say, we're going to begin to recognize how BCG can be used in a more precise fashion. And in combination therapy, what patients will benefit from those strategies as opposed to the blanket approach of delivering BCG for all patients? And many patients who are getting BCG who don't need to get BCG, frankly, particularly those with low-grade disease.

So I would say the BCG shortage was a huge driver and motivator for us as clinicians and clinical researchers to look for something else. And then just the opportunity to study so many agents in combination is certainly going to drive results, drive a change of practice, and a paradigm shift, I would say, over the coming decade as some of these larger studies begin to report their results.

Zachary Klaassen: Yeah, absolutely. And I think that table with the phase III BCG plus IO combos, particularly in the BCG naive space, is really exciting. Is there one or two particular trials you're interested in? I know there's a lot of activity in this space and a lot of opportunity. Is there one that, from your standpoint, you're really excited about?

Cheryl Lee: Well, I'm really excited about this sasanlimab. Our center is actually not a part of that study. I wish we were, actually. But the thought of the subcutaneous delivery of the immunotherapy to me is, again, more patient-centered. Right now, there's still a lot of uncertainty about what duration of therapy patients should receive as we think about PD-1 or PD-L1 inhibitors. There's also quite a big price tag attached to these agents.

And the question is, would someone with nonmuscle-invasive disease be more likely to accept that as a therapy if the side effects can be managed, accept that as a longer-term therapy, if they're not coming in, sitting next to people in an infusion unit with really advanced and metastatic disease? I mean, that's got to have a bit of an emotional impact for patients. So I think it's an interesting strategy. And so I'm very curious about that one. So I would say that that's what I'm closely watching.

It also is looking at—or I should say some of these other combination studies are looking at—intensity of therapy. Do we need all of the maintenance therapy if we have the combination of an immunotherapeutic agent? So that's another outcome that I'm very interested in learning about. So again, we're hopefully going to be more precise with our care for these patients with high-risk nonmuscle-invasive disease.

Zachary Klaassen: Yeah, absolutely. It's been a great conversation. I appreciate your time. Maybe a couple take-home messages for our listeners.

Cheryl Lee: I guess one, and maybe a few. One, I'm not saying that we shouldn't be using BCG now. We're not there yet. So we're all still using BCG. We don't have the data to support some of these other agents in the naive setting yet, but I suspect it's coming. So there are several agents that are competing with BCG as first-line therapy in patients who are BCG-naive. So I think we need to recognize that, participate in those trials when possible, and that allows us to advance our care.

I would also say that this use of combined therapy sounds incredibly fascinating. But we have to think about the toxicities for patients. And we have to think about the cost for patients. So those are two things that will bear witness out of these trials. And then I'll also just note that at some phase, we'll need additional research to have us think about drug sequencing. And which one of these agents or combinations of agents should be used now that we may wind up having first, second, third, fourth-line therapies. So BCG, you're under threat as a monotherapy.

Zachary Klaassen: That's a great concluding statement. Again, great talk. Thank you for your time and expertise. I know our UroToday listeners will really enjoy this discussion, and thank you, again, for your time.

Cheryl Lee: Great being here. Appreciate all of the discussion.

Zachary Klaassen: Thank you.