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Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm with UroToday, and we're going to have Kevin Kelly. I think everybody knows Kevin, well-known prostate cancer expert at Thomas Jefferson University in Philadelphia. And he's been doing some really provocative work, leading some provocative work, with AMG 509. Welcome, Kevin.

Willliam Kevin Kelly: Well, thank you, Oliver. It's a pleasure to be here.

This is the second time we've presented this data. Last year, we presented at ESMO the dose escalation phase of a new drug called Xaluritamig, which is a STEAP1-CD3, and what we call XmAb 2:1 immunotherapy in patients with advanced prostate cancer. This year, we updated this into what we call dose expansion slots to really try to optimize the treatment for this new CD3 antibody.

Again, as I said, for background, Xaluritamig is a STEAP1-targeted T-cell engager, and it is particularly designed to facilitate T-cell-mediated killing of STEAP1-expressing cells. And it's unique because it has two epitopes which actually bind to the STEAP1, then the CD3 to the T-cell. And for those who don't know STEAP1, it's highly expressed in prostate cancer and minimally expressed in other tissues in the body itself.

Well, this portion of the study, the first portion of the study, we defined the MTD, which is 1.5. Here, we were really looking at different types of optimizing that dosing schedule. Again, in the first part of the dose escalation, we did step dosing where we started at a low dose of 0.1, 0.3, then 0.5 to one. And again, we found different dosing schedules in this dose optimization part of the study here.

And again, there are three dose levels we looked at, and again, the one that was optimized the most—and we'll see the last one here at 1.5 where we started at 0.1, escalated to 0.3, went to one then 1.5. And again, we found that if you give it weekly versus every other week, the toxicities were less with the every-other-week, which we'll explain in a minute there.

But just the population we treated, this was a very advanced metastatic castration-resistant population. They had to have prior novel hormonal therapy and one to two taxane-based therapies. And the average patient had four or more therapies in the metastatic castration-resistant setting. Again, overall these were very advanced disease and around a third of the patients had liver metastasis.

Again, one of the major toxicities that we always get concerned about with T-cell engagers is cytokine release syndrome. Again, it was seen in around 75% of the patients, but it was really mild. And it was very interesting; it's only seen in the first dose, cycle one, in the majority of patients. As you go out further, the incidence of cytokine release syndrome decreases and that's because we do pre-dose them with steroids and we monitor them for the first 24 hours in the hospital. And if they need it, you can use tocilizumab which actually does reverse it. It was really surprising that the cytokine release syndrome was very well controlled in this population.

But I think that one of the adverse events that we are a little, well, I wouldn't say concerned about, but still need to understand it better, is the musculoskeletal inflammatory adverse events that we did see. This typically happens three to four weeks out after getting the doses and we did see it in around 76% of the patients. And we noticed a couple things.

One, if you actually hold the drug, it does get better. Two, steroids and tocilizumab do help it. And we found that doing every-other-week dosing actually improves the overall musculoskeletal-related events that we did see.

This is the dosing that is going forward for further testing, will be the step dosing to 1.5 then every-other-week dosing for the planned phase three trial at this time.

Overall outcomes of it, again, is that very similar to what we reported previously is that we see deep responses in PSA, PSA 90 responses in between 20 and 30% of the patients, PSA 50 responses anywhere from around 36% to 60%, receive RECIST response across the board going anywhere from 14 to 28% depending on the cohort we looked at here.

We also looked at, there were patients with liver disease. And around 20% of those patients have overall response in the liver, which is actually pretty impressive if you think about it.

Again, the durability of this, most of these responses are very durable. We haven't watched a lot of these patients for a prolonged period of time at this juncture, but we've seen long-term outcomes.

And I just want to mention Dr. Armstrong's abstract he also presented there. And it actually gave some of the long-term follow-up from Xaluritamig. Again, here's the efficacy results. Very similar to what we just presented here. Overall RECIST for over 67 patients was around a quarter of the patients, PSA 50% response at 53% and PSA 90% was 35%. Median radiographic progression-free survival was 7.7 months.

If we looked at the higher doses, that's where we looked at 0.75 milligrams and above at the target dose, overall responses were higher at 40% for overall RECIST response, PSA 50% response was 64% and PSA 90% was 45.1%. And median radiographic progression-free survival was 8.3 months. Actually very durable responses in patients.

We were able to get some long-term survival for this. Again, median follow-up of this group of 97 patients who were originally in the dose escalation part of the study was 27.9 months and median overall survival was 17.7 months, which actually is very comparable to other trials like the VISION trial, which showed an overall survival of 15.3 months. Very favorable there.

In summary, Xaluritamig continues to show clinical activity in patients with very advanced metastatic castration-resistant prostate cancer. Again, as there are some challenges with musculoskeletal toxicities which are being worked out, but again, this is very encouraging data and we're excited to move this forward.

Oliver Sartor: Gosh, Kevin, that looks like it could be practice changing. Now, of course, that's going to require a phase three. And I wonder if you might be able to talk a little bit about phase three plans and timing.

William Kevin Kelly: Yeah.

Oliver Sartor: Because that type of result in these far advanced patients, quite frankly it looks good.

William Kevin Kelly: Yeah, I agree with you, Oliver. And I think this study actually showed a couple of things. One, we broke a barrier in prostate cancer that there are therapies that can work in late-stage prostate cancer. And it was encouraging there.

And this is going into phase three trials and it's going to be a randomized trial, a two-to-one randomization to Xaluritamig versus cabazitaxel or AR switch. And we particularly wanted an active control arm there to compare it because I think it is appropriate to have an active control arm.

There'd be 675 patients enrolled in the study. It will enroll patients who progress on an AR and also one chemotherapy previously. And you could have had radioligand therapy beforehand too. I think it's a very practical trial and we're excited for it to get started.

Oliver Sartor: Terrific. Yeah, it's right in the PSMA lutetium space as approved through the VISION trial, and you should have reference there, and it looks to me like comparable activity.

William Kevin Kelly: Yeah.

Oliver Sartor: One of the things I think that might be concerning to people who will be administering the drug—maybe two things—it sounds like that first dose you've got to keep people under pretty close wraps. Did you say a 24-hour observation? Or how does that work? Do they actually go into the hospital?

William Kevin Kelly: Yeah. Currently, they're admitted for the first day of treatment. And they're admitted for 24 hours and monitored there. Again, we have been investigating how we can do this all as outpatient, but for safety purposes at this point, I think to move it forward until people are comfortable with these types of therapies, it's the safest for the first 24 hours to be in the hospital.

Oliver Sartor: Now, you're giving steroids, but then you mentioned tocilizumab. And toci apparently is able to shut it down pretty quickly, but do you know what percentage of patients actually required toci or is that a number you might have at the tip of your tongue?

William Kevin Kelly: I don't have it at the tip of the tongue. This was an international trial, so a lot of this was different country to country, but around a quarter to a third of patients will get toci.

Oliver Sartor: And just out of curiosity, when you admit them into the hospital, is this on some type of special service? Is this something that sort of requires a hematology consultant who might have experience with CAR-Ts and bispecifics? Do you kind of put them under observation on a general ward? Who manages this?

William Kevin Kelly: Yeah, the medical oncologist manages it. And I think that as we're getting more used to a lot of these T-cell therapies from other malignancies, there are special services in a lot of the hospitals that take care of these patients, but I think that we need to educate more medical oncologists and neurologists how to handle these types of side effects because it's very algorithm-driven. And once you actually know what to do and handle it a few times, it's very easy to take care of these patients.

Oliver Sartor: One of the things, and this sort of hearkens back to the VISION study, is a little bit of that patient selection. And I noticed you don't have any patient selection, like looking for STEAP1 expressors. Is that somewhat of an issue? Has anybody looked at the STEAP1 expression and seen if that's predictive of better responses or is it just like all comers?

William Kevin Kelly: We did no selection at all. We've done all comers. If you look at the expression of STEAP1 in prostate cancer and advanced disease, it's around 80% across the board. And they are looking at tumor samples and looking at STEAP1 expression and it continues to be pretty high. And I think there's development of a radionuclide STEAP1 to image STEAP1 expression, so that may be helpful in the future also.

Oliver Sartor: Yeah, interesting. In the radiopharmaceuticals, we are image-guided, but in this case, it's all comers.

William Kevin Kelly: Yeah.

Oliver Sartor: And I can't help but wonder about heterogeneity in the target and how that might relate to responses that you see. But it sounds like the people are kind of working through it now and probably even in its chemistry it's got pretty even expression.

William Kevin Kelly: Yeah, yeah, it is right now. And again, what will be very interesting is how these types of drugs will get engaged with the other therapies we're using. And I think that's the real exciting component is this: how do we actually do it with Pluvicto? How do we actually do it with other therapies? When do we need to do it? As you know, we are looking at it in earlier disease right now. There's a neoadjuvant trial that has initiated this month looking at patients to really understand a little more of the biology of it. There's a trial looking at rising PSA with this to see if, in minimal disease, if it actually changes the adverse event profile, but also looking at the activity. And again, as there are plans, it's looking at how do we actually salvage people who may not respond to PSMA lutetium or other radioligand. I think these are the studies that we really need to do because it shows a lot of clinical activity, but it's really how we're going to use it in daily practice that's going to be important. The sequencing.

Oliver Sartor: Yeah. You made a very specific allusion that the patients previously treated with Pluvicto would be eligible for the phase three?

William Kevin Kelly: Yes.

Oliver Sartor: Do you have much data in that kind of post-Pluvicto setting? Is that a subset analysis that has not been presented yet or is that something that has been presented and I just didn't see it?

William Kevin Kelly: Yeah, we didn't present it, Oliver, but there have been patients on study that have had it and have responded. The problem with the phase one, there's so many different cohorts and you don't have enough power to really make any one conclusion there. But anecdotally, we have had patients who've been treated with Pluvicto, have gotten this drug and have responded. I can tell you that.

Oliver Sartor: Yeah. Interesting. You've been around a good while, you've been involved with a lot of projects over the years. I can see that you're excited about this product and see the potential for utility in maybe even multiple settings.

William Kevin Kelly: Yeah.

Oliver Sartor: Let me congratulate you for leadership in these efforts and I know you're going to be a leader on the phase three as well. Hats off to you for doing some really good work.

William Kevin Kelly: Well, thank you, Oliver. It's a pleasure to work with everybody and I just want to move good therapies forward, right?

Oliver Sartor: Absolutely. All right. Well, Kevin, we'll wrap it up, but thank you so much for being on UroToday and sharing some of your thoughts on the AMG 509 and look forward to seeing more data when the time is right.

William Kevin Kelly: All right, appreciate it.