Raj Satkunasivam: Thank you, Ashish.
Ashish Kamat: So Raj, we've chatted about a few things. Talk to us now about EV-PRIME.
Raj Satkunasivam: Well, thank you for having me, first of all. So EV-PRIME is a unique trial that's phase 1b/2 that's combining definitive radiation with a backbone that's EV pembrolizumab. And I think it's very, very interesting now because we're seeing the arc of bladder-sparing tri-modality therapy really change from chemo radiation to chemo IO with radiation and now using an EV pembrolizumab backbone. So this is a trial in progress that's going to be presented by the group from UCSF and Dr. Khoshbin is the PI on this. And what's unique about this trial is it brings together EV with definitive dose radiation. So what they've done is to capture patients that are either ineligible for cystectomy or those who refuse cystectomy, those who would typically be going for tri-modality therapy, they would receive a full transurethral resection and they received two cycles of EV with pembrolizumab during the course of radiation. The radiation regimen that they've selected is 64 Gy and 32 fractions, so a conventional fractionation. And subsequent to this, they do have an adjuvant treatment.
So they're going to come back in with EV for three cycles and 15 cycles of pembrolizumab. Their primary endpoint is complete response or clinical complete response at six months. And we can talk a little bit more about that. I will add the 1b part of this is we really don't know how the toxicities of radiation and EV could potentially combine. And so they've thoughtfully planned out a dose escalation to inform their phase two dose.
Ashish Kamat: Yeah, but talk to me a little bit about the CCR. What's the definition that's going to be used? How are they going to assess it?
Raj Satkunasivam: Yeah, I assume that this is going to be a composite definition of both imaging and cystoscopy. I would hope that biopsies involved. It is unclear to me from the actual abstract itself, but something that I'll be looking into.
Ashish Kamat: Yeah, no, because one of the things that, as you know, we tackled at the international bladder cancer group that you were part of, and then we refined it with the JCO report from Milan, was the really strict definition of CCR, which is needed to make sense of these trials. I mean, again, in the real world, patients are going to come to us with partial responses and they're still going to want us to try to save their bladder. That's a separate issue. But if we're looking at the true clinical complete response, let me ask you, do you agree with the need for, say, biopsies? You alluded to the fact that you do, right? A TUR, negative imaging, whether it's MRI or CT depending on access, negative cytology at least, maybe utDNA, ctDNA. What's your sense about the relative importance of the imaging versus the biopsy versus the cytology and utDNA, ctDNA?
Raj Satkunasivam: I think that's a really important concept. We're all really focused on bladder preservation, and a big part of that is novel biomarkers, but I don't think one of them by itself stands. I really think we need to think of this as a composite biomarker, the additive effect. And so I think all of them are needed, potentially MRI together with mapping bladder biopsy together with the resection of the scar to really inform how that response has gone. And cytology, as you mentioned, and obviously sort of novel biomarkers, ctDNA is not so novel anymore, but utDNA is certainly getting a lot of attention, particularly at this meeting. So these are all important as a composite. I do think that the study design is pragmatic, right? A six-month clinical complete response is pragmatic, but I think you and I will both agree that we're going to be interested in the secondary endpoints. What does survival look like? What does bladder-intact status look like with follow-up? So those are all going to be important secondary endpoints.
Ashish Kamat: Yeah. I think that's a key statement there right there, right? Bladder-intact, event-free survival, because the patient really truly cares if they have their bladder, it's intact, and there's been no adverse events. And by adverse events, I don't mean toxicity, but metastatic disease, because no patient would like to have their bladder in place and end up with metastatic disease. And again, I say this not because our audience doesn't know all this, but I think combining something quite as powerful as EV and then taking a local consolidation aspect with radiation, I think is really... Well, I mean, kudos to the investigators for embarking on this. What would you like to see from this? If you had your crystal ball and if you could, okay, I would like to see this, what would you want to see from it?
Raj Satkunasivam: Well, I'd like to sort of step back a little bit and say, we're all now thinking about organ preservation, especially with the amazing response rates that we've seen with this EV pembrolizumab backbone therapy. So clearly the question is, how do we move forward with that? And I think this is one important aspect of trying to combine another additive therapy to move the needle forward because the way I think about it is there's 40% of patients who don't have that complete response. And how do we move that needle forward? Is it more systemic therapy adjuncts that could be combined? And we see some interesting signals in the metastatic space of combining novel PD-L1 inhibitors with EV pembrolizumab. And of course, CTLA-4 inhibition could be also an option. So I think there's a lot of interest in how do we add on to that. I see this as a very unique position to see how does radiation potentially synergize with this? Of course, we also need to know about the toxicity, and I think that'll really inform us in order to move forward from here.
Ashish Kamat: So let me put you on the spot a little bit, right? And let me sort of play a devil's advocate. And I'm giving you a heads up warning before I ask you the question. So we're seeing all these great results with EV pembrolizumab, really good pCRs. And now we're moving towards saying the pCR, let's correlate that with clinical complete response. Totally agree with all of that. I'd love not to have to take out a single bladder, right? But if you are getting such high pCRs with EV pembrolizumab, tell me a little bit your thoughts putting on the other hat, do we need radiation since observation might be an option, right? Talk to me a little bit about your sense there.
Raj Satkunasivam: I think you're totally on the ball here. I think that one of the most important trials that will come out is the Hoosier Network Group trial that is looking at EV pembrolizumab three cycles and assessing for complete response. And if they've met a very stringent criteria of clinical complete response, they go on to additive therapy and ongoing surveillance. And so there is no additional local consolidation that's planned. And so that'll give us a sense of the safety. It'll tell us how these patients do in the long term. It's a single-arm smallish trial, but it's going to be very important that's going to put forward the concept that you could just potentially get away with only systemic therapy. I think the concept of consolidation has to be clearly thought about as having pros and cons. I mean, potentially there is at risk cells for cancer, but at the same time, we risk overtreatment. And I think one of the most innovative trials in this space is what Peter Black's trying to do with the NEO-BLAST trial to randomize patients who've had a clinical complete response and to sort of see whether we can, first of all, convince people to be randomized. I think that's the first thing that we need to understand.
And if they do get randomized, then we can potentially generate data. Do you need to consolidate folks? And I think that's a very, very important question for our field because as we have done in GU and even thinking about prostate as an analogy, how that field has shifted and really, really understanding the pros and cons and understanding that there are drawbacks to immediate adjuvant radiation therapy in everyone. So that's an analogy that I think about in terms of overtreatment. I think we can select and better understand who actually needs consolidation. The other aspect to this is the non-muscle-invasive bladder cancers that are left because that allows us lots of opportunities to intervene and keep those bladders without potentially more toxic local therapies. \
Ashish Kamat: Yeah. No, I mean, great points. And again, the field is rapidly evolving. There's a lot of studies being done, as you mentioned, even in Europe, they're looking at basket trials with bladder preservation. So I think it's a great time for us to be doing this and helping our patients and finally maybe get to the right treatment, right patient at the right time. Raj, thank you for taking the time. Always a pleasure.
Raj Satkunasivam: Thanks so much.