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Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at M.D. Anderson Cancer Center. And joining us today is Marie-Pier St-Laurent from the University of British Columbia. Marie-Pier, welcome.

Marie-Pier St‑Laurent: Thank you. Yeah, really happy to be here. Thanks for inviting me to be presenting this research.

Ashish Kamat: Absolutely. So you had this trials in progress poster at ASCO GU, which was concluded last month, the NEO-BLAST study. So it's really interesting, your concept on neoadjuvant therapy for bladder cancer, followed by active surveillance versus treatment, because that's really where the field is heading. Patients want to try to preserve their bladder. So really interested to hear about your trial, and the background behind it, and where you think it's headed. So take it away.

Marie-Pier St‑Laurent: Perfect. Thank you. So yeah, so I'll be presenting this clinical trial, which was a trial in progress. We don't have any data to report. We're looking to be starting to enroll soon in Vancouver. So just before disclosure, I don't have any conflict of interest with this trial. It is an investigator‑initiated trial. It's funded by the Canadian Institutes of Health Research, so CIHR. And I do want to mention the acknowledgment here as listed for other supporting program.

So getting right away into the background a little bit and the rationale, as you mentioned, the field is moving towards that way of wanting to preserve bladder in those patients that perhaps could have a spared bladder. We know standard of care of most invasive bladder cancer is, up to today, cisplatin-based neoadjuvant therapy followed by cystectomy. But we know that does greatly impact quality of life of patients. And there is evidence coming from either retrospective studies looking at patients who decide that following a complete response to not have the cystectomy, with possibilities of good outcome.

Mazza did publish a retrospective study looking at five-year overall survival at 86% in this oddly defined population of scans and TURBT. There is currently a couple of clinical trials that are—I’ve listed four that actually, perhaps a fifth. I forgot to update. But there are ongoing clinical trials looking at active surveillance following CR. Briefly posted here before, you're probably familiar with them. RETAIN‑2 presented their preliminary results at ASCO GU. And I'm not going to go in details. I'm assuming some of you are familiar with those.

But there are interesting results coming out of them. RETAIN‑1 was negative. But the HCRN 16-257 trial did show approximately 96% metastasis-free survival at two years. So encouraging data here. There are some issues, however, in how we actually restage a patient. And that is one of the points I want to cover, the inaccuracy of the current ways of restaging. Here are just some basic data, again, wanting to show you the potential limitations we have.

So if we use CT scan and TURBT only to define what is a complete responder, we will have a lot of patients that will miss a window, miss the opportunity to have a definitive treatment. By that, I mean a lot of studies have shown that if you use TURBT and CT scan, about 20% to 30% of muscle-invasive cancer will have been missed. Those are patients for whom we have a good treatment of cystectomy that we want to offer.

There is also an older phase II prospective trial from SWOG, in which patients who were defined as CR by those means were offered to go for surveillance. Ten patients decided not to go for the surveillance, and one went for cystectomy. Six out of ten had actually still MIBC. So those are not perfect tools. Can we do better? So here is the proposition. I've listed some here. There is maybe some question marks with urine tumor DNA. But the question is, can we combine those modalities to increase our accuracy of restaging clinically following the neoadjuvant therapy and make bladder preservation safer?

Again, I want to bring up some data. There's more. I'm just surfing, just giving you some information, food for thought, and articles to go read if you are interested. So the Aarhus group did a lot in this field using biomarkers that you're familiar with, ctDNA. So this paper used the Signatera assay, which is a tumor-informed ctDNA in their cohort of patients, just under 100 patients, slightly more so in the 80 range, in which they had ctDNA done before the neoadjuvant chemo, and also before cystectomy. As you can see, the results being negative or positive did correlate with the outcome, either recurrence but also pathologic downstaging. So there's quite an interest here in seeing that the ctDNA can help us find patients who are likely complete responders with no minimal residual disease.

Again, from the same group, a later publication, more recent, used the C2i assay by Veracyte. This assay is also tumor-informed but uses a whole genome sequencing platform. And as you can see here, again, ctDNA performed before the neoadjuvant chemo, or after neoadjuvant chemo but before the cystectomy, correlated with overall survival and also with downstaging.

There is more, but I'm going to move forward to the next thing: bladder MRI. Can we better image the bladder than using conventional CT scan? Because we know CT scan is not good. So bladder MRI. Here are some data from PURE‑01 by Andrea Necchi. They looked at central review of the MRI and used NAC VI‑RADS—so VI‑RADS—scoring, but using NAC as an additional score of 0, meaning there's no lesion. They did correlate, again, with downstaging (odds ratio of 21, as you can see here, with a high area under the curve), and also having VI‑RADS 0–3 versus 4–5 correlated with the outcome, so not just only the downstaging.

So with that, putting all of those things together, what do we propose? So here is the trial schema that I'm deconstructing, and will bring you step by step into how we are going to do NEO‑BLAST. As the name says, NEO‑BLAST is neoadjuvant therapy for bladder cancer followed by active surveillance versus treatment. So what we're going to be doing is, patients who have muscle-invasive bladder cancer and who are eligible for systemic therapy that is standard of care at the time of the enrollment will be eligible to be enrolled.

The patients will undergo standard of care neoadjuvant therapy, and then, after completion, will be restaged. The restaging here, we are going to be including ctDNA, bladder MRI, TURBT—either if there's a lesion or the scar—and also a template biopsy, as well as conventional scanning. Those CT scans are usually done during the neoadjuvant therapy, so those will be done, as well, just to make sure there's no progression during the chemo.

Once they're restaged, if they are defined to be nonresponder—not complete responder—they will go for their conventional standard of care, so radical cystectomy. Or a patient could go for trimodal therapy if they fit the criteria, and then they go for surveillance. So here, nothing really investigational.

Here is what we're going to be more interested in finding: those complete responders will be randomized to either active surveillance or definitive local treatment. As you can see here, a couple of asterisks. Patients who are going to be randomized to definitive bladder treatment can either have chemoradiation or cystectomy. So basically, what we're going to be seeing here is, patients who have neoadjuvant repeat TURBT, with ctDNA and MRI negative, will be randomized to either chemo‑RT of the bladder or surveillance. A patient can decide to go for cystectomy, but we expect that the comparison is whether or not we need to treat the bladder with either radiation or cystectomy. The surveillance will be done as we’re familiar with for trimodal therapy, but with the addition of ctDNA. So as you can see, cystoscopy, CT scan, but as well ctDNA at those multiple time points will be done for all of our patients in the trial.

Because this trial is, let's say, a bit ambitious—will patients actually accept to get and be randomized? Hopefully, they will. But we are aware that there's a possibility that not everyone is going to be willing to go in this trial. So we're starting with a pilot RCT, or a feasibility phase II, to assess if patients get enrolled and complete randomization. If this is positive, we'll move on to a phase III trial, in which we're going to be looking at metastasis‑free survival at two years.

So this is the trial schema. And looking in details, for those who are a little bit more interested in the objectives here: as you can see, the primary of the phase II is feasibility to randomize patients. And then for the phase III, we'll be looking at two‑year MFS. We'll be looking at bladder-intact event-free survival, overall survival, acceptance of treatment allocations, and quality of life will also be recorded.

The sample size: basically, with a pilot trial, you can make it a little bit customized to your population you're going to have. So we're looking to enroll approximately 72 patients in our population in British Columbia. But then, in phase III, what is interesting is the number of patients who are actually going to be randomized. It will greatly vary as the years go, in terms of what regimen of neoadjuvant therapy we have. So the actual number of patients enrolled may change if we have novel—let's say chemo‑IO, or IO‑ADC—that have a CR rate that is higher. It is a noninferiority [study], event‑free survival, accepting a 10% difference between our two groups. And yeah, so that is pretty much it for me.

Just in short, I think this trial is important that we do. We know that the standard of care remains a neoadjuvant therapy with cystectomy, but we do have to consider bladder preservation and TMT in some of our patients who do respond greatly. We are expecting to have even more effective neoadjuvant therapy, so this will be pushing even more how we consider bladder preservation. But we need to know, do we need to treat this bladder? We don't want to miss the window of opportunity to cure a patient of this disease. So we need to get the answer to that question, and that's what NEO‑BLAST will be about. And we do think that there is, for that, a need of better defining what is a complete clinical response. So that's why we want to incorporate those ctDNA and MRI tools.

Ashish Kamat: Thank you so much, Marie-Pier. And really, it's an ambitious trial, and I think it will really answer a lot of important questions. So best of luck with getting it going. A couple of questions I had—and I'm sure you have thought of this, maybe just not presented it in the interest of time. So first off, in the patients that don't achieve your definition of CCR, which includes anybody with TA disease or small-volume CIS, are you thinking about maybe offering them intravesical therapy as a part of the active surveillance for those patients? Because obviously, you want to treat that, right?

Marie-Pier St‑Laurent: Yeah, it's a good question. So actually, perhaps you're right. I did go over that quickly. So a TA completely resected and ctDNA negative will be allowed to be a CR. So the only one is multifocal CIS. Perhaps that is applicable in that question. So we did not include BCG. I know all of the other risk-enabling schedules, let's say—RETain, for example, or Alliance, I believe, too—have BCG included. Speaking with some other investigators who've been doing those trials, I think some of the local recurrences were a bit the concern of missing a window of opportunity. So it is not in the trial plan this way. So a multifocal CIS is not going to be offered BCG. They can decide to go off trial and do off-trial treatment. The concern we had is persistent, let's say, CIS multifocal. Sometimes we feel they are resistant to the treatment we've been giving, and are we concerned that there will be a progression later on or a recurrence that persists? But it's a good question.

Ashish Kamat: Yeah, no, exactly. Because some of the follow-up data from RETAIN suggests that the non–muscle-invasive recurrences, even though they are truly non–muscle-invasive, actually end up with metastases. So there's something about the biology of that tumor.

Marie-Pier St‑Laurent: Yeah.

Ashish Kamat: And then the other question I had is, you obviously currently designed it in the era of current therapies. But with NIAGARA obviously having had a positive readout and it potentially being approved even in Canada for use, are you considering the post-CCR achievement?

Marie-Pier St‑Laurent: Adjuvant?

Ashish Kamat: Yeah, exactly. Are you going to allow patients to continue on adjuvant therapy as part of the study, or do they fall off?

Marie-Pier St‑Laurent: Yeah, good question again. So the way it is kind of designed, it's a restaging platform and treatment allocation, and it is not an investigation of systemic therapy. So if a patient is in that, let's say, sandwich—perioperative chemo‑IO with a subsequent couple of cycles of adjuvant—they will go on that, so therefore meaning to receive those adjuvant cycles. So it will be allowed. It will be encouraged that the patients, if they are in this CR response, to go on with this. Obviously, we'll make the data perhaps a little bit more—not messy, but we'll have to do some stratification in the response we have, and see the results depending on how many patients received which type of regimen. But it will be allowed to go on. And obviously, the same way if you have a nonresponder that fits the IO adjuvant criteria, if they had a cisplatin‑based regimen and they should receive adjuvant immunotherapy following, we'll recommend them to go for that. Yeah.

Ashish Kamat: Right. Well, like I said, congratulations on the trial design. Do you know when your first patient might be enrolled?

Marie-Pier St‑Laurent: I don't know yet. So I hope really soon. Actually, I'm about to finish signing some of our contracts in operations to get the approval. It's a bit of a logistics issue because we made this trial out to be somewhat centralized in Vancouver, but I want patients to be from all over the province to be eligible so that they can receive the standard of care up north if they're from a more rural community. But we can simply organize more regionally in Vancouver. So that just requires a bit more steps in logistics, but hopefully, it will increase the diversity of the patients we're going to be treating and actively enroll.

Ashish Kamat: Yeah, no, that's critical. And believe it or not, we have patients who listen to UroToday videos as well. If any patients from your regions are listening, you know where to find the trial.

Marie-Pier St‑Laurent: Yeah, always, Vancouver. Thank you so much for the invitation.