Mark Stein: Thank you so much. Thank you for having me here. It's really exciting to be here at ASCO this year and to be able to present data with the rest of my colleagues, obviously, on a novel T-cell engager that we are going to be reporting the first phase I results of and a really relatively large phase I trial, 174 men with advanced metastatic castration-resistant prostate cancer. And we're using a bispecific antibody, a T-cell engager, that targets a protein known as KLK2.
And so one arm of the antibody targets KLK2 and the other binds to the T-cell, to CD3 on the T-cell. So the idea is to engage with the prostate cancer, bring the T-cells into the tumor microenvironment, and then kill the cancer and benefit the patients.
Oliver Sartor: I love that. It's so simple. Just kill the cancer, it'll benefit the patient. Now these T-cell engagers, they've been around for a while. And we actually have some that are advancing even into phase III for prostate cancer, which you mentioned. This is a KLK2 targeted agent. So it's a little bit different. One of the things that's been a real problem with this whole class of agents is the side effects, the CRS. And that is not a pleasant topic for most T-cell engagers. But is this one different or the same?
Mark Stein: That's a great question. So the drug-- so I should actually-- people that are interested in just to pasritamig is the name of the drug, pasritamig. And the target again is a novel target. So it's worth explaining a little bit. KLK2, just briefly, it's similar to KLK3 is PSA. KLK2 is also a protease that's associated with the prostate membrane. As you said, it's a novel target. It's very specific for prostate cancer. So it's expressed in all-- really almost ubiquitously in hormone sensitive prostate cancer and in very, very high levels throughout the evolution of prostate cancer over the course of the disease.
Nothing is 100%. So sometimes as you proceed to very later lines of prostate cancer, that can be some heterogeneity. But KLK2 is a very clean target and very specific to prostate cancer and very well expressed. And so that specificity, I think, is part of what really allows for targeting it without a lot of off-target side effects that might be seen with other potential targets and distinguishes it, frankly, from some other targets in the field where there is off-- there is sometimes off-tumor expression.
Oliver Sartor: OK. But now CRS.
Mark Stein: So CRS.
Oliver Sartor: So where the bane cytokine release syndrome.
Mark Stein: No, it was.
Oliver Sartor: And this been the bane of the field. So let's talk about that very specifically, because that is such an important topic for people. And people in the outpatient setting.
Mark Stein: Sure. And some of our audience might not be as familiar as really something that, for instance, in the hematologic malignancies space, people are very, very familiar with and bring it in terms of solid tumors. CRS is cytokine release syndrome. It can really range from something as cytokine-driven, often IL-6, and often the initial manifestation is really fever. And then it can go on from there to hypotension or hypoxia or to more needing blood pressure support. And it is the most serious manifestation.
Having fever is grade 1 CRS and is easily manageable. However, even as in an outpatient setting, once you're moving on to something like grade 2 CRS, which involves lower blood pressure, needing to give somebody oxygen, then you're really talking about needing several hours of observation before resolution. And so, the goal here was to choose the dose in the phase I setting that gave good efficacy and also really didn't progress beyond grade 1 CRS. And in fact, that's ultimately in the phase I dose escalation trial. What we were able to achieve was finding that those doses through an iterative process that we do in phase I trials of getting to a really basically single-digit rate of grade 1 CRS, which could be easily mitigated basically with antipyretics.
Oliver Sartor: I want to be pragmatic. When you give this drug, how long do you have to keep the person under observation?
Mark Stein: You're watching for two hours afterwards.
Oliver Sartor: Two hours?
Mark Stein: Two hours, and then they go home.
Oliver Sartor: Can I give you a two thumbs up?
Mark Stein: I think--
Oliver Sartor: Two hours is two thumbs up. It's really good.
Mark Stein: It's amazing.
Oliver Sartor: Yeah.
Mark Stein: It's really amazing.
Oliver Sartor: All right. So tolerable from the CRS perspective, let's talk a little bit about the efficacy because of course, having a tolerable drug is not that important if it doesn't work. So does this drug work, and how do you measure it working? Tell us a little bit about that.
Mark Stein: And I'll tell you what. Maybe if I can just elaborate a little bit, because we are giving a little bit of-- the way the drug is given, just going back to the CRS and then this also plays into the efficacy as well. We give it as many of these drugs in the class are given in what's called step-up dosing. So initially, you start with a very low dose and then come back a week later for basically still a very, very low dose, really a tenth of what somebody would be getting in their 20th in the full target dose. And then by the third week, you're now giving the target dose. And those two steps of dosing, again, allow for mitigation of CRS. In addition, turned out that actually a lot of these similar drugs were given are being given subcutaneously.
Interestingly enough, this drug is being given IV. It allows us to get to a higher dose. And the patients in the IV dosing actually had even less of this CRS. And so then ultimately what was done is that we looked at different schedules and optimization and really the efficacy that you're asking me about that I think is in a sense most clinically meaningful is the efficacy and the cohort of patients. The total trial was 170 patients. And then we're looking at 40 or 40 that are in the efficacy cohort.
They were-- and that's where you see at the standard dose, which is 300 milligrams given IV once every six weeks. And you can say, well that sounds like not that. If it turns out that giving it more often is actually not optimal, that if you give it too often that you wind up getting an exhausted immune system, androgen induced cell death. So you want to-- every six weeks seems to be the right interval. And in that setting, the median progression-free survival is roughly 7.8 months. So--
Oliver Sartor: Let's talk about who you were treating at 7.8 months to be good or bad, depending on what kind of patient population.
Mark Stein: So that's an excellent point. So the population of men here, median lines of treatment was four lines of treatment. Everybody to be on this study had to receive at least one, in addition to being on androgen deprivation therapy, having castrate testosterone had to receive at least one androgen pathway inhibitor and the majority of patients had-- many of the patients had received chemotherapy.
And actually, there were patients on this study, particularly in the later cohorts who actually had received lutetium-177 PSMA as well. And so-- as people say, heavily pretreated population for the most part, in terms of the heterogeneity of the patients that were patients both with visceral and non-visceral disease. The drug does seem to have a higher response rate, PSA response rate in the patients with predominantly bone or nodal disease. And so-- so certainly, I would say the-- obviously, we need good targets for patients with visceral metastases and prostate cancer. And that, I think, winds up being an additional opportunity in the future as we develop the drug further.
Oliver Sartor: So what we have is a T-cell engager that you can give with very little CRS as a step-up dosing and to be able to discharge somebody two hours later.
Mark Stein: Correct.
Oliver Sartor: That has nice efficacy in heavily pretreated patients.
Mark Stein: Exactly.
Oliver Sartor: Can I say congratulations?
Mark Stein: Thank you. Thank you.
Oliver Sartor: That's really cool stuff.
Mark Stein: It's really an exciting time in the field.
Oliver Sartor: Well, I'd like to say thank you for contributing to our progress in the field. What happens next? You've done the phase I. You're going to go to phase II, III, IV? Are you going to be able to shoot for FDA approval? What happens next?
Mark Stein: So obviously, I have had the pleasure of working with wonderful collaborators at Johnson & Johnson, who ultimately, I think, are excited about this drug. And certainly, we'll look to develop it further and move it into registration hopefully so that we can really get this out to a wider population of men who need it. But yes. So certainly, those types of projects are actively in discussion.
Oliver Sartor: Very, very nice. So Mark, thank you for being here today. Thank you for being here today. And congratulations on a really impactful presentation that I think will help shape the field of prostate cancer going forward.
Mark Stein: Thank you. Thanks for having me.