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Alicia Morgans: Hi, I am so excited to be here today with Dr. Kevin Kelly, who is a professor of medicine and a GU medical oncologist at Jefferson in Philadelphia. Thank you so much for being here with me today.

W. Kevin Kelly: It's a pleasure.

Alicia Morgans: Wonderful. You actually gave a phenomenal presentation at ESMO 2023. It was the splash of the meeting. Really exciting because this was an early demonstration that there might be a way for us to work with immunotherapy and prostate cancer and come out on the other end with something that might be really helpful to our patient population, but a new approach. Why, to start, are new approaches needed for patients with metastatic CRPC?

W. Kevin Kelly: Absolutely. Again, is that we have gone through a lot of treatments in prostate cancer from what we call hormonal therapy to chemotherapy. Other therapies have not been uniformly effective in prostate cancer. Patients with metastatic castrate-resistant prostate cancer have very limited treatment options. Looking for new avenues to treat these patients is essential.

Alicia Morgans: Absolutely. Some of these cellular-based therapies I think are really exciting. The treatment that you presented is a completely novel way of approaching this disease. Can you tell me about that?

W. Kevin Kelly: Yeah, this is a new antigen, well it's been around for a while, called STEAP1. It's part of a family of different STEAP proteins one through four. STEAP1 is highly expressed on prostate cancer cells, but not on a normal prostate or other normal cells. It's a very good target for prostate cancer. We developed this unique drug here called AMG 509 or Xaluritamig, is a two by one monoclonal antibody that attaches to the STEAP1 protein on the cell surface with a CD3 construct. It actually attracts T-cells to induce cytotoxicity.

Alicia Morgans: Wow. This is a biTE therapy, right?

W. Kevin Kelly: Correct. Bispecific antibody, biTE therapy inducing the immune system to focus on the prostate cancer cell.

Alicia Morgans: Okay. Tell me a little bit about this phase one trial. Your primary endpoint, as I understand, would be usually adverse events. Let's start there. Tell me, in this trial, tell me about the patients that enrolled and then we'll get into their tolerance.

W. Kevin Kelly: Yeah, this was a first in human trial in patients with advanced prostate cancer who had progressed on one or two androgen therapies and also chemotherapy. Some patients could be entered if they refused chemotherapy, but it was a very advanced population of patients, had a median of four prior therapies before. If we look at this population, over half of them had visceral disease and a third of them had liver metastases, which we know is a very poor prognostic group of patients.

Alicia Morgans: How did they tolerate it? What were the adverse events that really kind of came to light?

W. Kevin Kelly: Yeah. Well, this was a phase one study. The objective of the phase one study is to push the dose to toxicity to find it. There are a couple of parts of this. First is we did a single agent dose escalation, and what we found is that there is a certain dose level, it was up to 0.3, which is not a lot that patients couldn't tolerate.

Then what we did is what we called step dosing. That means we started at a small dose, then did a larger dose, larger dose until we could get up to the target dose, which we felt to be therapeutic. In this trial, our step dosing started at 0.1, 0.3 to 1, then 1.5 milligrams, which is defined as the tolerable regimen.

In order to make sure none of the other toxicities like cytokine release syndrome, we had to make sure we had pre-medications, hydrate them, and we actually withdrew any hypertensive medications patients had. Once we did this and managed that, the major toxicity, which is cytokine release syndrome, was minimal. Usually grade one or two. After we did that, we did not see any grade three. In the whole study, there was no grade four or five toxicities we saw.

Alicia Morgans: So important. Tell me a little bit about how this treatment was administered. Was there inpatient time? Was this predominantly outpatient?

W. Kevin Kelly: Yeah, this is going to be a challenge because we monitor these patients very carefully. On week one, they're admitted for 48 hours. Week two, it was 24 hours. Subsequently, on a weekly basis. We're in the process of trying to manage this to turn it into an outpatient regimen, which is going to be critically important. I think that it's really because this is a safety study, we are trying to understand how to give this drug the best we can.

Alicia Morgans: Absolutely. One thing that you and I have both emphasized is that this is a safety dose-finding study. Sometimes we don't necessarily expect, actually in most situations, we would not expect to find efficacy in this kind of a study, though we do measure these kinds of things as well. Can you tell me if there were any responses to treatment which again, would not be expected in a phase one trial?

W. Kevin Kelly: Yeah, as you say, typically in a phase one trial, less than 10% of the patients ever have any type of response. We were very surprised, even from the lowest doses all the way through, every cohort of patients had PSA declines we saw. When we looked at higher doses, and we described higher doses as greater than 0.75 milligrams, which in preclinical models showed therapeutic levels, is his PSA 50 was 59%. PSA 90 was 36%.

More remarkable is the partial response rate was 41% in those patients. Median time, if you had a partial response on that, was 9.2 months. Not only we saw responses, but they were durable responses, which is really important. The other interesting thing we got out of this trial is if you had a response, you usually had a PSA response within four weeks, and you had a measurable response within the first two cycles.

This really was important because you induce the immune system, you get a response very quickly. All very encouraging data.

Alicia Morgans: Absolutely. When we think about treatments, we don't necessarily have that early feedback that something is working, particularly when it comes to something that may have some different toxicity profile. It is so important that we have an understanding of whether there's some sort of benefit here. Now, can you tell me, were patients treated over time as we see patients on study for a median of nine months? This would maybe require treatment over time?

W. Kevin Kelly: Yeah, I mean, doing a weekly treatment, as you know, it can be very cumbersome for patients, but patients came in on a weekly basis and got this and they tolerated it. We're going to have to think about how we do this in the future. What's the optimal scheduling of this? How do we actually combine it with other therapies? I think the importance of this trial is, it was always felt that prostate cancer was a cold tumor. Immunotherapy is not going to work. I think this really shows that it's not a cold tumor, you just have to have the right target for patients and you can get a response and your immune system will come up to the plate and show some activity.

Alicia Morgans: I guess we just need to think about it a little bit differently to figure out how to get that immune system engaged.

W. Kevin Kelly: That's absolutely correct, and I think that it's exciting time right now because I think we broke a barrier and you're going to see a lot more types of therapies like this, and we just have to work together to understand how do we optimize it.

Alicia Morgans: Wonderful. Well, I would love to hear from your perspective, what's the overarching message from this data and from this presentation at ESMO?

W. Kevin Kelly: Yeah, again, I would say there's a lot of hope for prostate cancer patients, for novel therapies coming down in the future. This really showed that immunotherapy has a role in prostate cancer and that yes, there are challenges with the treatments right now, but we have a lot of smart people out there going to solve this. I have a lot of confidence that some of these therapies will impact on and improve the lives of prostate cancer patients.

Alicia Morgans: Well, I don't think I've heard a better message yet, so thank you so much for that. Thank you so much for the work that you do and for your expertise today.

W. Kevin Kelly: All right, thank you. My pleasure.