Evan Yu: Good day again. It's great to be here at Uro Today here at ASCO 2025, and right now I'm here with Dr. Kevin Kelly, who's a Professor of Medicine and Oncology at Thomas Jefferson University in Philadelphia. So fly, Eagles fly, right? No, not for me. I'm a Cowboys fan as many of you know. All right, sorry. We'll get back onto the topic here.

William Kevin Kelly: That's a sore subject in here.

Evan Yu: Very sore for me, but good for you guys. Okay, so let's talk about the big randomized Phase 3 trial that you have going on here. So Xaluritamig, is that right?

William Kevin Kelly: Xaluritamig, yes. Xaluritamig.

Evan Yu: Xaluritamig.

William Kevin Kelly: You got it.

Evan Yu: I said it right there. So, okay, Xaluritamig. I read your cancer discovery paper, but before we get started talking about the randomized Phase 3 trial, why don't you tell everyone what the drug is and the mechanism of action? It's pretty darn interesting, so would love to hear more about it.

William Kevin Kelly: Yeah, Xaluritamig is two-by-one engager to STEAP1 and CD3. Again, its pre-clinical models showed that there's significant activity on prostate cancer there. We started the Phase I study several years ago with dose escalation. We did a single agent to escalation at first and got up to around 0.3 milligrams and hit toxicity there. And subsequently we had to go back and do step dosing and really define the dosing for this. But we did define optimal dosing for Xaluritamig because we did see some of the side effects that you do see in typical T-cell engagers, some of the CRS. We did see musculoskeletal pains, and we had to adjust the dose, but we finally found a dose starting at 0.1, going to 0.3 to 0.75, then 1 to 1.5 on a weekly basis. Typically, patients are admitted to the hospital for the first week of therapy, then it can be managed as an outpatient afterwards.

Subsequently, we did dose expansion cohorts there to really, really define the dosing regimen so we can take it on to a Phase 3. Again, we found that you take the same dose escalation, 0.1, 0.3 to 0.75 to 1, then 1.5 milligrams and go every other week with that. And when we did the dose escalation studies there and expansion, what we did show is that the every-two-week regimen was better tolerated. Major toxicities were CRS that we did see, but it was very manageable. But one toxicity that was new for us was the musculoskeletal toxicities, which is really thought to be a myofasciitis. It can be controlled with steroids, and also just giving a break from the drug itself.

Evan Yu: So is STEAP1 highly expressed on the muscle fascia? Is that why it is?

William Kevin Kelly: There's some mild expression on there, but etiology is not really known. But what's really interesting, you stop the drug, and it's totally reversible. There's no long-term toxicity from it, and as a GU oncologist, we don't often deal with this. So this has actually been new for the field to really understand some of these side effects from Xaluritamig. But what was interesting about this drug is the clinical activity we saw on [inaudible 00:03:38], you know, PSA50s at 50% across the board, PSA90s, 28% of the patients. If you look at RECIST criteria, 20%. But what was really interesting is the durability of these responses for months, durability there. And when we looked at overall survival for those patients in dose escalation over 17 months... All right, so I think that it does have clinical activity, and it was encouraging data, so this is why we actually developed the Phase 3 trial.

Evan Yu: Okay. And remind me, you said it required inpatient hospitalization. Was it three days for the first dose, or was it a full week?

William Kevin Kelly: No, no. Essentially as we were going forward in the Phase 3, it's the first dose you're in the hospital. Everything else is outpatient now.

Evan Yu: Okay, so first dose in the hospital, but how long in the hospital? Is it overnight, or...

William Kevin Kelly: 24, 48 hours.

Evan Yu: Oh, okay, so it's just 24, 48 hours, and then everything else is outpatient.

William Kevin Kelly: Everything else is outpatient. You still have to pre-medicate them, and you have to monitor them. And I think that's one of the things that we need to start understanding is when you have a CRS effect, it's six to eight hours after you give the dose, so you can't give it at three o'clock in the afternoon and have an outpatient. So you have to really arrange these patients early in the morning so you can monitor during the day so you can go safely home.

Evan Yu: Okay. And in your earlier study there, how many patients did you need to give real high doses of steroids to Toci, all the stuff for CRS?

William Kevin Kelly: CRS is typically only in the first cycle, the majority of that, and only a small fraction that actually had a severe Grade 3 or 4 CRS.

Evan Yu: Okay.

William Kevin Kelly: All right.

Evan Yu: So it was a very small number of patients that really, really needed it to seek treatment for it.

William Kevin Kelly: Yeah, that's correct. Yeah.

Evan Yu: Okay, that's good.

William Kevin Kelly: Yeah, but again, even with a Grade 2 you have to be careful because when treat CRS, intervention early is the key, to recognize it and intervene early.

Evan Yu: Great. Okay, let's jump into the trials in progress poster and this randomized Phase 3, so why don't you lay the groundwork for it?

William Kevin Kelly: So it's a randomized international Phase 3, open-labeled study looking at Xaluritamig versus investigator's choice of Cabazitaxel versus an ARPI in a two-to-one randomization. 675 patients will be randomized. And what was unique about this study is we wanted an active control arm, so 50% of the patients have to have Cabazitaxel in that versus an ARPI. So we want to show against an active control arm, which I think really highlights how we want to make sure that we have clinical activity with Xaluritamig. So kudos to the company and everybody who designed that. All right?

Evan Yu: So if you're not at close to 50%, you're going to actually restrict enrollment of patients that the investigator says they'd want to use an ARPI? And you're saying "No, we only want patients that you wouldn't want to use Cabazitaxel for." Is that right?

William Kevin Kelly: Yeah.

Evan Yu: Okay, got it.

William Kevin Kelly: Yeah, and I think that that's been one of the criticisms for a lot of the Phase 3 trials, not having an active control arm, okay? Again, the patients who are qualified, those are metastatic castrate-resistant prostate cancer, progressive on ARPI, and also had Docetaxel in the metastatic castrate-resistant population. You could have had it when you're hormone-sensitive, but you have to have a taxane in the castrate-resistant setting.

Evan Yu: Got it.

William Kevin Kelly: Again, the primary endpoint is overall survival. We're looking at progression-free survival, response duration, and we have quality of life components in there also.

Evan Yu: Okay. What about Lutetium-177-PSMA? Is it allowed?

William Kevin Kelly: Yes, it is.

Evan Yu: Is it mandated?

William Kevin Kelly: No.

Evan Yu: It's not mandated, right?

William Kevin Kelly: No, it's not mandated. The reason is because of international trial, all right, so you can't mandate things like that. But it is allowed, you just have to have a three-month washout.

Evan Yu: Okay. And other things like radium, no problem? They can receive that?

William Kevin Kelly: They can receive that, but anything radium, lutetium needs three months washout.

Evan Yu: Okay, three months washout. Got it, got it. Okay. Well, that sounds like a very, very exciting trial, and the results could be game-changing down the road.

William Kevin Kelly: Well, I think that what was interesting is that Xaluritamig shows us that prostate's not all cold tumor, and there's hope for immunotherapy in prostate cancer. And I think that there's a lot of other similar molecules coming down the road that are immunotherapy-based, and that's great for the field, I can say.

Evan Yu: Let me ask you this question, though. Let's say the study is wildly positive. Down the road, do you think it'll be a barrier, the fact that inpatient administration, and maybe not every medical oncologist right now is used to managing CRS, also a lot of urologists still manage advanced prostate cancer. How much of a "put it in the water" type of agent is this versus a niche agent?

William Kevin Kelly: Great question there. Right now we have trials going on in [inaudible 00:09:07] setting. We have rising PSA patients, and there is a Phase 3 going on in patients with... Well, there's actually hormone-sensitive trials going on. And what's interesting is most patients don't want to get off the drug. Even though you have the musculoskeletal toxicity, which is really the main thing that we see, they'll bear with it, and because they know when they come off, it's reversible. So I think it's more of a mindset at how we can actually address that, and I think there's ongoing research to understand that pathophysiology a little better.

Evan Yu: Okay. You think we'll get there? You think it'll be-

William Kevin Kelly: I think we'll get there. I mean, there might be better immunotherapies in the future, but I think it'll get our field to start thinking about it a little more, the prostate.

Evan Yu: Now, I would've thought that would be a good question to wrap up with, and that's what I was thinking, but then something else popped into my head. What are you going to do about STEAP1 expression, and how much does that matter? I got to ask that question now that's popped into my head.

William Kevin Kelly: Yeah, yeah, yeah. Well anyway, we actually took a look at it; didn't make any difference.

Evan Yu: Okay, so for this study, you're just going to do it, but you guys are still going to look at it, though, aren't you?

William Kevin Kelly: We've looked at it in the Phase 1, and really there was no correlation between responses or not. The really interesting about these drugs, if they really work, they work in the first four weeks. That PSA drops right away, and we haven't seen the correlation between the expression and a response.

Evan Yu: Do you think it's because STEAP1 expression is a little more dynamic than we think? Maybe it comes and goes, or do you think it's constant?

William Kevin Kelly: Well, we just published a paper looking at what changes STEAP expression, and again, it is related to antigens, not necessarily to antigen receptors. So understanding the role of STEAP1 is going to be critically important because it can actually modify thinking about how you can modify and change the expression of that in the future.

Evan Yu: Okay, great. Well, hey, thanks so much for taking the time. I'm super much looking forward to the results. I think it's wonderfully exciting, and...

William Kevin Kelly: Well, it's up and running, and there's quite a few patients on it already.

Evan Yu: Yeah, well, I'm looking forward to seeing what ends up happening with this.

William Kevin Kelly: Good. Great.

Evan Yu: All right, thanks again, Kevin.

William Kevin Kelly: Thank you.