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Alicia Morgans: Hi, I'm so excited to be here today with Professor Michael Morris, who is joining me from Memorial Sloan Kettering at ASCO 2024, where he talked recently about a rapid oral presentation. This was an hK2-targeting antibody with a radioisotope actinium conjugate. Tell me all about your presentation, please.

Michael Morris: Sure. Here's a little bit about what, first of all, the target is. hK2 or human kallikrein 2, is very similar to something that many, many people will be familiar with, and that is hK3, which is also known as PSA. So hK2 and PSA are very closely related, but there is an important difference. hK3, or PSA, is generally soluble. That's why we can measure it by just doing a quick blood draw. hK2, on the other hand, has both a soluble component and as well binds to the cell membrane. I think your viewership should be familiar with this, with a membrane-bound target from PSMA. So similar to that, there's a part of hK2 that's on the cell membrane that is ready to be docked to by a targeting molecule that can be carrying a radiation payload. So that moiety is this drug, which is JNJ-6420, it's an antibody that targets hK2, but it preferentially binds to the membrane-bound form. So even though there is soluble hK2, the drug is binding primarily to the hK2 that's on the cell membrane where it's internalized.

And then like similar to other radiopharmaceuticals, it brings the drug in where it irradiates the prostate cancer cell. In this case, this is with an alpha emitter, which is different than the beta emitters, which currently are FDA approved. Alpha emitters basically release more energy in a smaller distribution or lesser amount of tissue penetration. In boxing terms, the alphas have a stronger punch, but shorter reach than the betas. And so that's really the basis of what this trial is. The patients on this study, they are patients with metastatic CRPC. All of them had to progress through at least one ARPI. Around 60% of them had chemotherapy in the past. About 30% of those patients had two regimens of chemotherapy. So these were pretty advanced heavily pretreated patients. Unlike with lutetium that is PSMA directed, there is no companion imaging biomarker here. So these are unselected patients. And the primary endpoints of this study were essentially defining the RP2D and safety as a primary endpoint, secondarily looking at anti-cancer effects.

Alicia Morgans: Just before we get into the results, and this is a phase I study, so the primary purpose for these studies is to define safety profiles. But I am excited to hear if you were also able to demonstrate some early efficacy. But before we get into that, as I said, you mentioned that there's not a biomarker that we can use from an imaging perspective. Is hK2 really very ubiquitously expressed on prostate cancer cells? Is it expressed anywhere else? Can you tell us a little bit about that?

Michael Morris: It really is very similar to PSA. So it is expressed across the full natural history of prostate cancer from the untreated patient with primary disease to the extensively pretreated patient with metastatic disease. Now, we don't know as much about the heterogeneity of hK2 expression as we do about PSMA expression. We did, however, just complete a phase 0 study to look at the expression in humans that was published in the Journal of Nuclear Medicine last week, in which we did have PSMA scans to compare to the hK2 imaging. And there's good tumor localization. Unlike PSMA, there is not salivary gland expression. And so when we think about the small molecules with alphas, we think of xerostomia as being a dose-limiting toxicity, not so with hK2 because there is really very little in the way of salivary gland uptake. So I think that from a patient selection perspective, we don't know how much our data would be improved from an efficacy standpoint if we did use some imaging selection criteria. But, like most targets, we don't have PET imaging to allow for that companion diagnostic treatment qualifying biomarker like we do with PSMA.

Alicia Morgans: That makes sense. And if expression is similar to PSA in these adenocarcinomas, which are the majority, obviously, of prostate cancers, this would be a very commonly expressed protein. And perhaps that contributes to some of the results that you found. So tell me a little bit about the findings from this phase I.

Michael Morris: All right, so it's important to realize, first of all, phase I, the aim is to find the phase II dose or the phase III dose.

Alicia Morgans: Yes.

Michael Morris: Because, again, going to this concept that if you have a good response, you have less disease that you need to irradiate. As long as you're saturating the tumor binding sites, you don't need as much therapy as a patient who has much more extensive disease.

Alicia Morgans: I just want to make sure that everyone hears this. It's so fascinating, I think, to take the traditional oncologic perspective and couple that with a nuclear medicine and radiation oncology perspective, where we might start at a higher concentration and a bigger bang for our buck, and then, over time, adapt. And I think that a lot of our hope is to continue to do this with radiopharmaceuticals, radioligand therapies to be able to have that better personalized balance of treatment efficacy and tolerable risk.

Michael Morris: Yes.

Alicia Morgans: So it's fascinating that this study, I think, is teaching us so much about that in addition to this particular molecule.

Michael Morris: Absolutely. It teaches us as medical oncologists to begin to think like radiation oncologists in terms of what's the cumulative dose exposure and what's the fractionation of that?

Alicia Morgans: Yes.

Michael Morris: And we know from the radiation world that activity and fractionation matter, and so we need to begin to think about those concepts as drug developers. And I think that that's actually intellectually challenging for a lot of folks because they're thinking, "Okay, so what's the dosing interval?" And the answer may be one dose until the patient needs more therapy.

Alicia Morgans: Yeah.

Michael Morris: But we also have to recognize that each of these molecules is different. So a small molecule will behave differently, perhaps some of the durability of the response, and as well some of the toxicity that we see, is because we're using an antibody, which has longer clearance than a small molecule. So you just need to keep your mind open with each agent. That you have to sort of reset the rule book and treat each agent as it comes for the properties that it has.

I should say that, like PSA, we know of no hK2 expression in the lungs or the pleura. This is probably not an on-target effect but rather relates to circulating or captured alpha-emitting drug in either the pleural space, the pleural fluid, or the parenchymal lung. So you have to think about what the on-target tox is and as well what the off-target tox is, knowing that it's an antibody, knowing that it's an alpha, and thinking both in terms of an infused drug, but also the dose, I shouldn’t even say the dose, but the activity of the drug.

Alicia Morgans: Yes. Well, this is absolutely fascinating and I think there's so much for us to learn and so many questions that we'll have for you over time as we continue to learn about this particular agent as well as others that are coming through the pipeline, so we’d love to have final comments from you as we wrap up.

Michael Morris: I think that the final comment is about hK2 as a target. Everyone's known about hK2 for a long time because we know the PSA and the molecules that are related to PSA and PSA metabolism and development. But when we think about hK2, I don't want your viewership to be thinking just radioligand therapy. This is a nice target for prostate cancer. And so when we think of our families of targeted therapies, we have CAR Ts, we have other immune therapies like T-cell engagers, and we have radiotheranostics. So when you have a new target and it looks like it's working well, I would think more broadly we have a new family of therapies for prostate cancer rather than this being a one-off for this particular agent.

Alicia Morgans: Absolutely. And antibody-drug conjugates as well, potentially coming down. I mean, obviously this isn’t an antibody conjugate, but a radioligand, there could be other ADCs with more chemotherapeutic type payloads.

Michael Morris: Sure. I didn’t even mention ADCs, but you’re absolutely right. There’s a whole world of ADCs that now have a new credentialed target. Totally correct. Yep.

Alicia Morgans: Well, it's an exciting world in which we live, and I so appreciate you taking the time, of course, to share it at ASCO while we were there, but also to educate all of us today. Thank you so much for your time and for your expertise.

Michael Morris: Thanks so much for having me, Alicia.