Vadim Koshkin: Yeah, absolutely. Well, thank you first of all so much for having me here today and for giving me the opportunity to discuss this trial. It's really a clinical trial that we're very excited about at UCSF, and with our whole interdisciplinary team between urology, radiation oncology, medical oncology, and I'm really, really excited to discuss it today. This trial, I really see it as being at the intersection of two major trends right now in how we maybe approach or think about patients with muscle-invasive bladder cancer. Right? On the one hand, we have now much better systemic therapies I think that we did historically. And there's of course data presented at this meeting, data presented yesterday from EV-304. There was earlier data that's for muscle-invasive patients treated with EV pembrolizumab prior to radical cystectomy. And these are cisplatin-eligible patients. Of course, we earlier saw data at ASCO for cisplatin-ineligible patients. So, that's now really going to be the standard for muscle-invasive patients. And we're seeing, I mean, really impressive pathologic complete response rates, right?
Sam Chang: Oh, unbelievable. More than 55%, and actually almost two thirds of those that had their bladders actually removed in actually the true analysis in terms of bladder removal. So, a big change is going on.
Vadim Koshkin: Yeah, for sure.
Sam Chang: And so, how does this trial fit into that?
Vadim Koshkin: Yeah. So on the one hand we have this, just much better systemic therapies. On the other hand, there is also a lot of interest actually in bladder preservation. Right? And that's a trend that's also been, I would say, ongoing for the last several years, patients with muscle-invasive disease. So with this trial, when we first started thinking about it, even a few years ago when the first really promising data with enfortumab emerged, it's really this trial combines those two things. Where on the one hand, we're giving patients EV and pembrolizumab, but instead of taking them for radical cystectomy, we're combining it with bladder-sparing radiation. That was really the idea and the genesis behind this trial.
Sam Chang: And so, are we currently enrolling patients now? Tell me where we're at and which patients are being looked at and who are being excluded.
Vadim Koshkin: Yeah. So this is a phase-one/two trial, we're in a phase 1B, we're doing dose escalation of enfortumab from really the lowest dose we would use, which is 0.75 mg per kg, to 1.0 to 1.25, which is the full dose that we use, well, really for both metastatic and muscle-invasive patients. And of course, the idea there is to make sure that enfortumab is safe as part of this approach and to find a safe dose, basically. And so this is in phase 1B, this is the standard three-plus-three design. And then the main endpoint of phase 1B is of course safety based, and two, to also find the recommended phase-two dose. And then once we have the recommended phase-two dose, then there is a larger dose expansion. It's actually a pretty large dose expansion, almost like 30 patients at the recommended phase-two dose. And that will hopefully give us some important efficacy benchmarks, as well as confirming safety of this approach.
And hopefully we'll, again, see some robust responses like what we're seeing with EV pembrolizumab in other settings. And I should also highlight just the overall design, where patients get EV and pembrolizumab initially for two cycles. So that's six weeks concurrent with radiation, this is the standard fractionation that's about 32 fractions or six weeks. And then subsequently, they get another three cycles of EV pembrolizumab, so five cycles of EV pembrolizumab total. And that matches up somewhat well, I would say, to what we do with muscle-invasive patients in other settings like prior to radical cystectomy. And then for the remainder of one year total treatment, patients will just get pembrolizumab. So, a total of one year of pembro.
Sam Chang: So what are the endpoints for this study? I mean, we've got safety that we're gathering. What are we looking at in terms of a response? Obviously, safety features. What are we looking at in terms of endpoints?
Vadim Koshkin: So in the phase two, the dose expansion portion of the trial, really the primary endpoint is clinical complete response at six months. That in itself, I think is an interesting discussion even from some of the sessions at this meeting yesterday and discussing what exactly clinical complete response means in this setting. That's an evolving definition, but usually it means some combination of negative imaging, negative cytology, and of course, negative cystoscopy. And just confirming that there's no local recurrence of tumor, and of course, importantly, no distant recurrence of tumor.
Sam Chang: And then secondary endpoints for this?
Vadim Koshkin: And then the secondary endpoints are the longer term clinical outcomes we really care about. So disease-free survival, cystectomy-free survival, of course in this patient population, and overall survival as well.
Sam Chang: So, what do you think is going to happen five years down the line? Are we going to do this concurrent therapy, or are we going to do EV pembrolizumab first and see what happens? What do you think?
Vadim Koshkin: It's a really, I think, important and fascinating discussion right now. And this is a question I think a lot of us are thinking about and a lot of people are asking and actually, a lot of patients are asking. Right? Radical cystectomy is a procedure many patients don't want, right? And it's a curative procedure for many patients, right? But if we can find an alternative, then that's the direction we want to go in, right? And so I think with... Again, there's probably a difference between maybe how I would approach this and what I think generally would be happening. Right? So for a patient who comes in with muscle-invasive disease, and we think about the general treatment paradigm, which is, at this point, we're going to start EV pembrolizumab. That's really going to be the new standard. And then probably after that, we're going to consider them for radical cystectomy, right? But many of these patients, again, probably up to two thirds, are going to have a pathologic complete response to the radical cystectomy, which then begs the question of, should they be getting that surgery? Right?
And we also have other important tools like ctDNA to maybe inform that decision as well. So I think many patients, by the time they reach the three, four cycles of EV pembrolizumab, and if they have a pretty good response and maybe the urologist takes another look and there's no tumor left, many patients would be considering not getting surgery at that point. Right? And so I think then we have to think, well, is it enough to just get this systemic therapy? Right? Some of the other relevant discussions in this space is that from other important trials like RETAIN and RETAIN-2, for instance, we do see that many patients, though their distant disease is pretty well controlled with adequate systemic therapy, they do have local recurrences. So probably, and those, well, as we all know, can cause a lot of morbidity and a lot of issues as well. Right?
Sam Chang: Right.
Vadim Koshkin: So I think in addition to really a good systemic therapy, we need some form of localized control, and that probably would be provided by radiation. So I think many patients will be getting this in sequence. So EV pembrolizumab and then some form of consolidation maybe with radiation, or maybe just surveillance with regular cystoscopies, right? But then this trial here then I think also gives us an opportunity to think about it in a bit of a different way, where maybe upfront we do both, EV pembrolizumab and radiation. And if we again see that this approach is safe, and then we see efficacy. Then I would probably, with the right data, of course, be offering this approach. So instead of waiting to see what happens with EV pembrolizumab and then considering radiation, maybe just doing them both upfront, and then some additional systemic therapy after completion of radiation like in this trial, and then hopefully we just watch them after that.
Sam Chang: I mean, you can see the risk obviously are we're going to overtreat, but the advantage being, hey, during this cycle of treatment, we're going to be able to decrease the local recurrences significantly. So you have this balancing arm, and then just as you talked about, if you can determine upfront, okay, who's not going to just have the complete CRs with EV pembrolizumab? If you could then say, okay, we're going to go both concurrent, decrease the chance of any local recurrence, I think especially that's why I think your morbidity and possible complication data is going to be really important. If there's really not much difference in terms of signals, vis-a-vis EV pembrolizumab alone, you can see, well, gosh, I really have dropped my chance of having my bladder removed even more by doing this concurrent therapy. So, where are we now in the trial? We're still in the phase one. Have we gone to phase two yet or where are we now in trial accrual?
Vadim Koshkin: Yeah. So the trial right now is still in dose escalation, so we just reached actually the second dose level cohort. So pretty good safety data, no issues really with the lowest dose of EV, so now we're at the second level of 1.0 mg per kg. And yeah, so hopefully we'll again continue this dose escalation and maybe even by the end of the year, wrap that up and hopefully then go to dose expansion.
Sam Chang: Ah, fantastic. Vadim, thanks so much for spending some time with us. We look forward to seeing what these results show, because the paradigm for treating patients with muscle-invasive bladder cancer has evolved dramatically over the past few years. And this will only add to our knowledge of, okay, what do we do with these patients, how we can minimize the morbidity, and really give them a chance for a real cure?
Vadim Koshkin: Yeah, absolutely. Thank you so much for having me.