Sarah Psutka: Gem-iDRS.
Sam Chang: Yes. Gemcitabine intravesical drug-releasing system?
Sarah Psutka: Yes.
Sam Chang: Gem-iDRS-
Sarah Psutka: There we go.
Sam Chang: ... plus cetrelimab, versus cetrelimab alone, as a monotherapy, in the perioperative setting, so neoadjuvant and cystectomy. And this study, though, focused on specifically... I think the key points were, "Can we do the cystectomy in a timely fashion? And how are the outcomes? Are there more complications? Are there more issues?"
Sarah Psutka: Right.
Sam Chang: So, first of all, thanks for being here, and tell us a little bit about your presentation, your poster.
Sarah Psutka: Well, thanks for having me, Sam. So this is an update of what we presented at the Game Changer session at the European meeting last year. So Andrea Necchi and I had the fortune of leading SunRISe-4. Again, this was a neoadjuvant study for patients who were cisplatin-ineligible, who were going to undergo radical cystectomy and couldn't or refused to get cisplatin, which we all know 50% of patients can't receive cisplatin. Of course, after the data we heard this morning, we're going to have a lot of other options based on our novel perioperative platforms with the EV-pembrolizumab. But barring that, how do we offer patients who can't get cisplatin an option for neoadjuvant therapy? So, it's an immunotherapy with or without this intravesical chemotherapy delivering device. But when we were thinking about the study design, I wanted to work with the company, and did it. They were really supportive of this.
I was like, "If you're going to validate a new neoadjuvant therapy paradigm, you need to prove that it's not going to delay time to cystectomy, it's not going to make the cystectomy harder or not possible, and it's not going to increase the complications associated with the surgery, because we already know that cystectomy is such an incredibly complex surgical procedure with such a very substantial burden of morbidity and potentially mortality for our patients. So, if we're defining safety of a novel neoadjuvant therapeutic paradigm, we've got to prove that you're not disrupting or making the surgery more risky." So, this is actually just a sidebar analysis. The primary analysis, obviously, has been presented by Andrea a lot, and we know the pathologic complete response rate. You have about 10% increase, 38% in the investigational arm.
Sam Chang: The combination arm, mm-hmm.
Sarah Psutka: I think that that was obviously what was the key question is, "Do you get out a good-
Sam Chang: Just make a difference. Yeah, right.
Sarah Psutka: ... benefit by putting this device in a bladder in a patient who's already receiving IO?" The key take-home messages from our analysis were, one, about 85% of all patients got to cystectomy within the pre-specified time window. The average median time to cystectomy in both the cetrelimab alone and the cetrelimab plus gem-iDRS arm was about 13 weeks. There was only one patient who had a delay related to this... that was attributed to the systemic therapy. There was one patient in the cetrelimab-only arm that had hematuria and had a delay to getting to cystectomy. That is good news. We're not with this novel IO plus/minus agent-
Sam Chang: Pushing off or delaying.
Sarah Psutka: ... pushing off cystectomy because we know that time to cystectomy is a really-
Sam Chang: Is really important.
Sarah Psutka: ... important quality metric in the management of muscle-invasive bladder cancer. Second point is we know that, with traditional cytotoxic chemotherapy, patients get pretty beat up on that regimen. You know, you see somebody when you indicate them from surgery, and you see them after the four cycles, and they oftentimes have lost a significant amount of weight. I did some work when I was at Northwestern in Cook County, and we showed that patients lose, on average, 6% of their muscle mass between just the 110 days that they're getting that treatment between imaging.
Sam Chang: Neoadjuvant treatment, right.
Sarah Psutka: And this is already a patient population that has a burden of sarcopenia of about 70%. So, you're making these patients sicker.
Sam Chang: You're stressing them out even more, absolutely.
Sarah Psutka: You're stressing them, and we know that that has implications for how they're going to tolerate the surgery, their length of stay, and their recovery trajectories. This study wasn't designed to evaluate this question. So we had to rely on surrogates. So we looked at change in performance status from study entry to right before surgery. We looked at change in creatinine and kidney function. We looked at change in albumin, which is a nutritional surrogate. We looked at change in hemoglobin, which can be viewed as a nutritional surrogate. And also, it's actually associated with muscle mass. And basically demonstrated that there was no significant change-
Sam Chang: So no significant decline-
Sarah Psutka: ... in any of those premises-
Sam Chang: ... with the combination therapy.
Sarah Psutka: ... in the combination arm or-
Sam Chang: Or the cetrelimab arm.
Sarah Psutka: ... in the cetrelimab alone arm. I think that's just edifying that, especially as we are moving towards really incorporating immunotherapy in our perioperative systemic therapy for this patient population, this is some data that can suggest and support the safety of that.
Sam Chang: Right.
Sarah Psutka: And then point three is, "Do you increase the risk of postoperative complications and, most importantly, postoperative deaths?" And the punchline is there were no deaths after surgery at either 30 days or 90 days attributed to the treatment, the neoadjuvant therapies.
Sam Chang: Oh, that's very reassuring in that, just as you said, you already take a population that's already compromised from the diagnosis standpoint.
Sarah Psutka: Right.
Sam Chang: You stress them out even more. The parameters appear to be pretty good. And then, the death rate, at least 30 months... or 30 days.
Sarah Psutka: 30 days, yeah.
Sam Chang: It's not significantly different or affected, which is fantastic.
Sarah Psutka: Exactly. There were deaths after surgery, as there are, unfortunately. The 90-day mortality risk after radical cystectomy is somewhere in the 2% to 5% range, depending on the study you read. So there were three deaths, two in cetrelimab-only arm, one in the combination arm, in 30 days and an additional four, two in each arm, and they were all related to cardiopulmonary arrest, one case of peritonitis, hypoxia. So, these are unfortunately-
Sam Chang: Recognized.
Sarah Psutka: ... recognized risks of the radical cystectomy, but we didn't see a signal where exposure to either of these two agents in the preoperative setting exacerbated that risk.
Sam Chang: That led to that. So, no IO-based complication.
Sarah Psutka: Correct.
Sam Chang: No combination of the chemotherapy in the intravesical drug-releasing system. So I think understanding that, especially as we are incorporating different neoadjuvant strategies, we're going to be doing that, this at least gives us a basis to say, "Okay, if we go to cystectomy..." And that's a question now we're going to have to struggle with.
Sarah Psutka: Right.
Sam Chang: But if we do, we seem to be able to get these patients, at least with this combination, in a timely fashion to cystectomy and that we're able to actually get them do the cystectomy, that nothing from that pretreatment that was a combination of the gemcitabine plus the cetrelimab, or cetrelimab alone.
Sarah Psutka: Well, yeah, I think certainly, especially in this study design, looking at whether or not the gem-iDRS increased any kind of local inflammation rates that might have made the surgery more challenging or made a risk of higher iatrogenic injuries, for sure.
Sam Chang: Absolutely, yeah.
Sarah Psutka: But I do think we see... I take a big step back, but look at the kidney literature. When people started doing cytoreductive nephrectomies in patients who were getting IO-based upfront systemic therapy, there were a number of studies that came out that suggested that that operation, all of a sudden, became significantly more challenging and risky, and there were some studies that were really urging caution, centralization of performing that operation. I know we both do that surgery all the time. You know that those... You see loss of surgical planes. You see increasing desmoplasia. Yeah, it's a different operation.
Sam Chang: Right. No question.
Sarah Psutka: And I personally, in my experience having done now some consolidative surgeries in EV-pembrolizumab, I think it's safe to say that there's definitely changes in the tissue quality, but it's still something we can do safely.
Sam Chang: Right.
Sarah Psutka: And the fact that we're not making our patients substantially more vulnerable in that preoperative period is really important.
Sam Chang: Yeah, I think that it further validates this treatment strategy.
Sarah Psutka: Right.
Sam Chang: If we had significant delay and/or worse outcomes in terms of complications, perhaps survival would still be important, but boy, at the sacrificing cost of more complications, more issues, definitely is reassuring that this data really actually showed that they can be done.
Sarah Psutka: And I think the one question as you're looking at all of these perioperative systemic therapy trials, how many people are falling off and not getting to cystectomy? The studies this morning with EV-pembrolizumab, there... with any of these treatment regimens, there are patients who fall off the mark during neoadjuvant therapy, and they either because of treatment-related adverse events or they... We call it provider or patient preference-
Sam Chang: Sure.
Sarah Psutka: ... or progression.
Sam Chang: Progression of disease, sure.
Sarah Psutka: You see patients not getting to cystectomy. So it's really important that if we are engaging people in this preoperative systemic therapy, that we're not disproportionately, essentially excluding patients from what is, at this point, the definitive treatments. We'll see how that changes-
Sam Chang: Look like.
Sarah Psutka: ... in the coming years.
Sam Chang: Sure, sure.
Sarah Psutka: But it's edifying at least to see in the SunRISe-4 study basically high 80% of both arms made it to cystectomy on time and safely.
Sam Chang: Yeah, within that 13... or median time of 13 weeks and getting-
Sarah Psutka: Right.
Sam Chang: No, I think we owe you personally a lot, Sarah, for all the work that you've done in terms of perioperative preparation, understanding the importance of your frailty evaluation, the sarcopenia, nutritional, improving perioperative attempts with rehabilitation both before, after. The work you've done is fantastic, and this fits in basically hand-in-glove in terms of, "Hey, let's make sure, as we develop new paradigms, that we actually get to the treatment that at least in the past, historically, has been the definitive treatment."
Sarah Psutka: Right, yeah.
Sam Chang: So thanks again, Sarah, and look forward to talking to you again.
Sarah Psutka: Thank you so much, Sam.