Vignesh Packiam: Of course, thank you so much for having me and inviting me to give this talk. At the SUO, there was a lot of buzz about bladder cancer, as you mentioned. There were not major reports from intermediate-risk trials, but there were some updates in trial design and some new trials that became available, so I'd like to highlight what is going on in that space. Thank you for the introduction today, and I'm excited to talk about updates in intermediate-risk NMIBC. This was presented at SUO. And at that meeting, there were not major updates in trial results, but there were some interesting new trials that were presented and we learned about some new trial designs that are out there. As an overview, today I'll go over current guidelines, what the standard-of-care options are and what currently off-label options are available to us to use in this patient population. There are a couple of trials that recently finished accrual, and that's exciting as we're going to see their results very soon. There's a whole slew of ongoing trials and there are some new trials in development that look very interesting. Different ways to categorize these trials and data, but the way I do it in my mind is to divide it between trials that are using traditional adjuvant therapy after TURBT, or those that are looking at chemo or now immuno-ablation, which I think is very beneficial for our patients.
To kick it off with some guidelines, intermediate-risk NMIBC, at least by AUA criteria, includes patients with higher risk, low-grade lesions, those that are recurrent within a year, larger lesions, multifocal, the rare low-grade T1 entity. And AUA guidelines also includes small papillary, high-grade TA lesions as well. And that's important to know because some of these trials have different inclusion criteria. Some will exclusively enroll low-grade patients while others use the AUA criteria. I always like to show these guidelines and give Dr. Chang a shout-out. The guidelines recommend that patients could get induction intravesical chemotherapy or immunotherapy, so we do have a lot of options for these patients. But because of the ongoing BCG shortage, the AUA, SUO and other guidelines really recommend prioritizing chemotherapy in these patients if possible. We know from large meta-analyses of randomized controlled trials that BCG generally works better than Mitomycin C, but in the intermediate-risk space, Mitomycin has a two-year recurrence-free survival of about 60%.
So are there ways to further optimize Mitomycin, especially if there's recurrence after prior treatment? This is an FDA-approved therapy that we're able to utilize as of this year. It's called Zusduri. This is reverse thermal Mitomycin C. A typical substance like an ice cube, when it's cold, it'll be solid. This is the opposite. When it's cold, it's a liquid, and when it hits body temperature, it solidifies into a gel that then has slow release and increased contact time with the tumors, which allows for chemo ablation. The two prospective studies that supported this agent were the ATLAS trial and the ENVISION study. And the ENVISION study showed that there was an 80% complete response when this agent was used in a chemo-ablative fashion, so there were marker lesions that were left behind and it was able to get rid of the tumors 80% of the time, and this was durable in over 80% of patients as well. The UTOPIA trial was kind of a follow-up study to ENVISION. It's assessing a reformulation of UGN, and this is easier for the company to manufacture and easier to distribute. It was really reassuring to see that the complete response rate in this study of about 100 patients was almost identical to what we saw in ENVISION, 78% complete response.
This is something that's FDA approved and available for our patients now. What about BCG and Gem/Doce? This was a study that we did with three institutions that retrospectively looked at about 180 patients that either had BCG or Gem/Doce for intermediate-risk NMIBC, showed the two-year recurrence-free survival of BCG was 70% and Gem/Doce was 75%. Although BCG is an option, again, we generally try to avoid it in patients with low-grade disease so that we can reserve it for higher risk patients with our ongoing shortage. Gem/Doce, this data looks really reassuring and really in line with what we see in high-grade disease. But the main problem with Gem/Doce is the logistical challenges, especially in community practices, to actually deliver the medication. This is a novel agent NDV-001. This is a reformulation of Gem/Doce that gets instilled simultaneously into the bladder, solidifies into this sphere drug matrix, and then slowly dissolves over the course of days to weeks. The company is currently developing a study in the intermediate-risk space where they're randomizing about 300 patients to either induction NDV-001 or observation. PIVOT-006, this is a very successful trial that was run through the SUOCTC. It accrued very rapidly, so kudos to all the investigators that helped to enroll patients onto the study, and to the SUOCTC, which is clearly having a lot of success. This looks at the agent, Cretostimogene, which we're starting to see promising results in the BCG-unresponsive state for.
And this was a phase-three trial, 367 patients, randomized to either adjuvant Cretostimogene after TURBT or surveillance alone after TURBT. And notably, the arm that had surveillance, if there was a recurrence, they were allowed to have resection and then receive Cretostimogene. Another important caveat for this trial is that it uses the AUA criteria, so it did allow for small high-grade papillary lesions, which is distinct from some of the other trials out there. This finished accrual a couple months ago and we're all very excited to see what the results show. MoonRISe-1, this is ongoing, although I believe it's very close to finishing accrual. This is looking at the J&J drug releasing system, which has, instead of gemcitabine like their Inlexo system, this TAR-210 device slowly elutes erdafitinib pellets. This study is randomizing over 500 patients to either this TAR-210 device or investigator's choice of Mitomycin C or gemcitabine. This study is an adjuvant study, so TURBT is done before these agents are given. The other distinction with Pivot is that this is exclusively in a low-grade population, so this does not allow for patients with small high-grade papillary tumors. ABLE-32, this study has been around for a while, also being run through the SUOCTC. This is looking at nadofaragene, which obviously is approved in the BCG-unresponsive space for a few years.
Now it's being tested in the intermediate-risk setting and it's being randomized to observation in patients with intermediate-risk NMIBC. SURF302, this is kind of a newer study concept that was looking for more investigators at the SUO. This is an oral FGFR3 inhibitor, so it's kind of unique in that it's not an intravesical therapy. This is a marker lesion study of 90 patients where they're doing dose escalation of this oral regimen to see if they can chemo-ablate tumors. We know that FGFR3 mutations are very common in low-grade disease. This trial is in development and hopefully will be activated in the near future. This is looking at Anktiva, otherwise known as NAI or N-803. And this is an immuno-ablative therapy where about 40 patients will be randomized to either N-803 plus BCG or N-803 plus gemcitabine. We're starting to learn some of the potential immunologic effects that gemcitabine gives as well, so there's some rationale to that combination. I'm hopeful to see this ablative trial be activated in the near future. There's a couple studies in Europe that I wanted to highlight. This is the COBRA study. In Europe, using Mitomycin in different forms is relatively popular. The DaBlaCa study was an interesting report where they looked at intensive chemo-ablative Mitomycin C.
Instead of a traditional once a week for six weeks instillation, patients got three instillations of Mitomycin per week for two weeks. So all of that six treatments was compressed from six weeks into two weeks. And it showed some success as a chemo-ablative agent, so this is a follow-up study in a larger cohort to assess that strategy. And I think this study is really cool also, also being done in Europe. This is an organoid study where patients get TURBT, their tumor is plated into organoids in the lab, and then they drip different chemotherapy onto them to see what is going to treat these tumors. And these are all ones that are available. Epirubicin, we don't use it as much in the United States, but Mitomycin C, gemcitabine, docetaxel, very commonly used here. Based on the results of the organoid sensitivity testing, then the patients will go on to receive whatever the most favorable agent for them is. And I think this is a really cool precision medicine study that we should be seeing more of. In summary, we have growing amount of options for these patients. In the intermediate-risk setting, unlike the more aggressive BCG responsive high-grade setting, we really are caring about patient's quality of life. We want to get rid of their cancer, but especially these small low-grade tumors are generally not lethal, low rate of progression, so that's something that we're looking for in all of these studies as well. Thank you.
Sam Chang: Great summary. It's clear why your lecture gets so much attention during the SUO. Well, let's talk about strategies. We'll start off first with risk stratification. As you look at these cohorts, you talked a little bit about the slight variation. For instance, the inclusion of the small high-grade in the CG study, some studies just doing low-grade papillary, et cetera. So as we look at these different studies, tell me how you think about intermediate-risk disease. What I mean by that is, do you really think these small high-grade TA should be intermediate risk? Should they all be high risk as the IBCG has talked about in terms of a new classification of intermediate risk? Tell me how you think about this cohort and then how it influences your treatment choices.
Vignesh Packiam: I really loved the SUO session because it had a couple other talks that were looking at this exact question. There's one talk about IBCG risk stratification, which tries to understand heterogeneity and put patients into new buckets within intermediate-risk disease. There's also a really nice debate about whether or not these small high-grade papillary lesions should be included in the intermediate-risk space or not. At least for the high-grade question, I think I understand both sides of the argument. At least with the caveats of selection bias and retrospective data, it does seem like those patients have a little higher risk of progression compared to those with low-grade tumors. That being said, we have all seen these tiny little high-grade papillary tumors in practice that do not behave that aggressively, so do they really need the full blast treatment? Do we have to waste BCG when we could use other therapies that are also effective on that? As to risk stratification, I think that's the real puzzle. I applaud efforts like the IBCG, trying to come up with real-world practical guidance for that. These patients can have such a variety of different treatments. Last week I did a TURBT that took seven hours in a patient.
Sam Chang: Oh my gosh.
Vignesh Packiam: Entire bladder was covered with these massive, low-grade papillary tumors. Now, that patient probably does have a risk of progression because it's hard to believe the pathologist is going to look at every single chip.
Sam Chang: Every single piece, sure.
Vignesh Packiam: And maybe that patient deserves BCG or the most aggressive treatment that we can give them, versus a patient with these literally one millimeter separate papillary tumors who probably doesn't need anything and could have active surveillance as well. So there's so much heterogeneity, we're trying to learn about it. To be honest, I think a lot of us use gestalt. There's not a perfect way to really decide-
Sam Chang: Whether you're right. And I think you can't underestimate the importance of experience, but at the same time, you can't chalk everything up to experience because we're always surprised by different patients. So I think some of the work that you've done in terms of validation with certain biomarkers will be very helpful as we really try to determine who is higher risk, who is lower risk. I think any risk stratification table system, obviously the people on the edges, the lower versus the higher within each group is very different from the one smack dab classically in the middle. But I think at least the buckets give us a better idea as opposed to nomograms and algorithms that I think many people don't use, because although we have a lot of options, we have an idea of, "Okay, this is a high risk, this is a low risk, here's the bucket in the middle," and then we go from there. A question I have for you, totally theoretical, is, should we look at these intermediate-risk patients? Should we really actually be doing trials where we compare them to, say, just surveillance without therapy? In other words, we have these chemo-ablative treatments. I mean, should we in fact, randomize them into just observation alone versus chemo-ablation? And yes, chemo-ablation can be effective, but what about these tumors never give patients difficulty for years and years? What do you think of that kind of trial process and what do you do with the patients that you do surveillance? What's your trigger to actually do something?
Vignesh Packiam: I think the trial design is very complicated, partially due to heterogeneity in this space. We actually had the PIVOT study and the MoonRISe study open at the same time here. And patients had trouble choosing between the studies because of what was in the control arm. It was hard for them to hear that this is not that aggressive a disease, it's okay to maybe just get no treatment after TURBT but at the same time, we're offering this really powerful treatment that we're seeing great efficacy in the BCG-unresponsive space for. And I've heard mixed things. I've heard investigators say the opposite problem too, where patients would prefer not to be randomized to anything in the control arm, but it all just has to do with their tumor. If they've had recurrences, I think they would have an eye to being more aggressive, versus someone with a relatively new diagnosis. If we're telling them that the disease is indolent, then they may be interested in just observation.
Sam Chang: Yeah, I think it's that whole... And then you throw in visualization with blue light versus white light. Have there always been tumors there that you've just missed, et cetera? So it really talks to the amount of data we're getting, but the difficulty in sometimes parsing it out for every specific situation, so Dr-
Vignesh Packiam: One thing I want to add in the mixed-grade setting, I think we need to do a lot more research on this. Obviously, the pathology guidelines have changed over time. We used to have the three-tier system, now we have high and low grade. There was some controversy about mixed grade. I think the cutoff of 5% high-grade component to be called high-grade versus low-grade, a lot of this is anecdotal and I think we need more evidence for it.
Sam Chang: No, actually, really good point. And hopefully with, honestly, integration of AI and big data, it will have a clearer picture of really what that means. And no, it's an exciting time, it's a learning time. And so we are, in the field of urology, very, very fortunate to have leaders like you actually pushing that research forward. So as always, great to see you, great for us to have a chance for you to be able to share some of your thoughts in this intermediate-risk category, and look forward to seeing you again soon.
Vignesh Packiam: Great to chat, thank you so much.