Oliver Sartor: Hi, I am Dr. Oliver Sartor with UroToday, and really a special pleasure to welcome Mike Morris, well known throughout the prostate cancer field. Mike is the leader of the Prostate Cancer Group at Memorial Sloan Kettering, longtime investigator, longtime contributor in many, many ways. Hello, Mike.

Michael Morris: Hi, Oliver. It's such a pleasure to be here today. Thanks so much for the invitation to chat, and about new targets and alternative payloads as well to what we are most commonly using now, which is lutetium and PSMA. And as you know, we work together on a lot of different projects and it's really a pleasure to be able to discuss this one.

Oliver Sartor: Well, thank you. What we're going to talk about today, Mike, is something a little different. PSMA is well known to everyone, but you've been working very specifically on a target called KLK2, or some people call it HK-2. First of all, what is this target?

Michael Morris: Well, when we think about PSA, PSA is really a member of the kallikrein family and it specifically is human kallikrein-3. Now, PSA is a molecule that is used in screening. It's used in tracking responses or progression to therapy, and really it's part of standard of care in so many different contexts.

Now, PSA is fully soluble, and so you can just measure PSA or HK-3 by virtue of a blood draw. Human kallikrein-2, encoded by the gene KLK2, is very closely localized to the PSA gene and is co-expressed in as part and parcel of PSA production. But there is an important difference between human kallikrein-2 and PSA and that is that HK-2 or KLK2 is not just soluble in terms of its expression, but is also expressed on prostate cancer cell membranes, and has an external domain that is available for targeting by drugs that target the surface molecules of prostate cancer.

So it's an important target for, not just radioligand therapy, but could be used for bispecific antibodies, could be used for ADCs, CAR-Ts and other therapeutic modalities that target the surfaceome of prostate cancer.

Oliver Sartor: That's a really nice explanation, Mike. And the surfaceome is really a hot topic these days because as you alluded to, we can target it in a variety of different ways, for the radioligands, whether bispecifics, whether, or not even CAR-Ts, ADCs.

So being able to understand the surfaceome and how it evolves over time is really important. Let's talk a little bit about this KLK2 expression. Is it something that is modulated up or down by hormonal therapy? Is it something that is expressed more or less during the disease journey that patients will undergo with repetitive treatments? Do we know much about that?

Michael Morris: Great question. So the easiest way to measure expression of human kallikrein-2, is basically through a blood draw because it is co-expressed with PSA. And so you can do a blood draw and assess HK-2 pretty accurately, but you're only measuring the soluble component.

And it does vary according to AR signaling just like PSA does, and reacts to various AR modulators as does PSA. But does that really reflect what's going on at the level of the cell membrane? And for that you do need imaging. Now, we did a phase zero imaging study using indium-111 and an antibody that we had developed at MSK. And that was really interesting because even in patients who had low PSAs on suppressive AR signaling drugs, they still were imageable in terms of looking at the membranous component of HK-2. And what's interesting is that this targeting molecule does preferentially bind to the membrane-bound form as opposed to the soluble form, which is really important because you don't want to lose all your drug binding to the liquid reservoir of the molecule.

So, I'd say it's a complicated question that you're asking because we need to think about the various compartments of expression. And the liquid compartment isn't the key compartment. It really is the membrane-bound compartment that we need to be attentive to. And there is no commercial imaging agent by which to answer your question with good data. So we only have this small phase zero study that I had done with Neeta Pandit-Taskar, who's one of our nuclear medicine physicians, a few years ago. And it does look like the target's still present even in those with low serum PSA values.

Oliver Sartor: Interesting. So we're about to delve into the radiopharmaceutical world here in just a moment, but I think what you're saying is that even though you're going to be targeting the cell with a radioactive isotope for therapy, we're not using a theranostic component by imaging what we treat. So let's go into the KLK2 treatments, understanding that we're not imaging the patient before we treat them, which is a little bit discordant with the typical theranostic principle that we use for PSMA.

Michael Morris: You're absolutely right. I mean, this raises a really important question, which is: when do we need an imaging agent and when don't we? So one could make an argument that really having PSMA PET has been of great advantage to the development of PSMA-directed therapies.

As was brought up, though, by the original discussant for the VISION trial, who was, is Mary Ellen Taplin, something in which screen failures ranged in VISION between 13% and PSMAfore at 8%. One might say, "Well, that's a pretty low screen failure rate. So do we need the imaging agent?" And I guess that raises the question for the new theranostic pairs that we're developing is, when does it become economically not feasible to do imaging, as opposed to heterogeneous expression of a target or patients who are rarely expressing targets? When do we really need the imaging agent?

As you probably, you and I have talked about this a lot, I'm a big fan of having the imaging agent, and would like to have an imaging agent in order to really understand the drug development of therapeutics that target HK-2. But the reality is that economic concerns do play a role in these decisions, and so far there hasn't been anyone on a commercial basis to support developing a true PET tracer for this target. And so we do not have one.

Oliver Sartor: Mike, let's talk a little bit about the therapy you presented at ASCO, a very nice phase one, in which there was activity of KLK2 using the antibody with an actinium payload. And I wonder if you might just briefly go over this concept a little bit.

And during the presentation, you began to talk about adaptive dosing, which I thought was quite interesting. So I wonder if you could help our audience understand a little bit about the treatment itself, and a little bit about the adaptive dosing, which I think are two interesting topics.

Michael Morris: Sure thing. So what we had presented was a phase one dose escalation study of the actinium radiolabeled therapeutic iteration of the drug in men with metastatic castration-resistant prostate cancer. And as you aptly point out, there was no imaging threshold because there was no imaging component to this.

Nonetheless, we did see that the drug was quite active, and indeed its level of activity was such that even with a nominal amount of dosing, we could even dose just once, we were seeing pretty durable responses to it.

Now, this brings up a really important issue that is on the tip of the tongue of everybody doing theranostic drug development now, which is how much dosing is too much and how much dosing is too little for theranostics. There is this concept that, in theranostics, that really this is a form of radiation therapy, and so the radiation dosimetry, that is, the amount of radiation delivered to the tumor, is really key to optimizing how we dose this type of therapy.

Now, the dosimetry is optimized when the tumor has the most copious expression of target in order to capture the radiation. And most of the treatment effect in theranostics is actually delivered in just the first couple of doses of the full course of radiopharmaceuticals. And Ken Herrmann did a really nice job in the VISION trial showing that the majority of the full dose of all six doses of PLUVICTO is actually delivered in the first two doses. More is delivered in the sum of those two doses than the ensuing four doses for the rest of the treatment course.

So the idea of adaptive dosing is to dose more radiation therapy up front. But then, when it looks like the tumor dosimetry is diminishing because the volume of tumor is diminishing, you hold off in order to preserve that optimal ratio of tumor dosing to normal tissue dosing. You want to minimize the amount of radiation that's delivered to the normal tissue.

And so for the HK-2 trial, we were seeing dose-limiting toxicity with the sort of repetitive dosing according to the model that we had established with PLUVICTO, which was just you keep dosing every six weeks, and until the patient's marrow or other toxicity declares that you can't dose more, you just keep going.

So we saw, emerging from a cytopenia, and also really significant clinically, interstitial pneumonitis, emerge with just a repetitive dosing schedule. And so instead, what we did is we reduced that in order to deliver enough radiation in order to adequately treat the tumor, but not so much radiation that we were damaging normal organs such as the lungs or the platelets.

And that led us ultimately to the dosing schedule that we are now exploring, which is just a single dose of the drug, and we don't redose until the patient has relapsed following that. So I think that this concept is now really widely discussed, and being included in future clinical trials as we design those in order to front load the radiation to the tumor, and then really back off dosing as the ratio of tumor dosing to normal organ dosing becomes less favorable as the tumor shrinks.

Oliver Sartor: Really interesting concept, Mike. I grew up in the chemotherapy era where dose-dense chemotherapy regimens are very popular and the more is better type regimen. I worked with Vince DeVita who was known to say, "full dose on time," and so there was no idea that you would delay the dosing to allow the target to re-express itself to allow for more optimal dosimetry. That was like a totally different concept.

So this is really a paradigm change and I salute you and the KLK2 team for being able to introduce this paradigm change into an alternative target, not PSMA, and to make some progress. Now, this trial is still ongoing as I understand it, and you may have a few comments about where we are, and then I'll briefly switch topic about another KLK2 related topic.

Michael Morris: Sure, yeah. The trial is still ongoing, and right now the primary treatment population being explored is the chemotherapy-naive CRPC population in that same group of patients captured by the PLUVICTO label for PSMAfore. So those who have post-ARPI but pre-chemotherapy. And we're continuing to explore how to optimally treat patients, what's the right dose and what's the right schedule.

I think that it's funny that you bring this up. You and I were both trained in a chemotherapy dominant era. I think that this concept of adaptive dosing is very difficult for most medical oncologists to wrap their heads around, because we are used to thinking about a model where the tumor is shrinking, and for every dose of chemotherapy that you give, the tumor is still getting as much treatment.

And so ultimately, if you just keep treating and if the drug keeps working, you get down to a cell count of zero, and that's the whole concept of dose-dense chemotherapy. It just doesn't work that way in radiopharmaceuticals. And I think that this will take some training of our community to understand this concept in order to embrace that adaptive dosing isn't really giving less of a dose to the cancer. It is sparing the normal organs' toxicity while optimizing the treatment of the cancer. It's not a dose optimization in the way of how little can we give the tumor. It's how much can we give to the tumor, but how little can we give to the normal organs?

Oliver Sartor: Interesting topic, Mike. Before we wrap up, KLK2 on the surfaceome seems like a very good target. And I wonder if you might make a brief intro, without going into the details because it's a separate topic, on the bispecifics that are engaging CD3 and KLK2 in order to treat the cancer. And tell us what this bispecific stuff is targeting KLK2.

Michael Morris: Sure. So there is a parallel drug development pathway using KLK2 as an immunology target. As is probably known by most of our audience, bispecific antibodies look like the first immunotherapeutic drug class to be active in prostate cancer. I think that the first awareness of this was in regards to a STEAP-1 targeting agent that was presented by Kevin Kelly at a previous meeting, in which there was a startling amount of activity, both in terms of radiographic responses and PSA declines using a STEAP-1, CD3, bispecific antibody.

But as we explore other targets than PSMA and prostate cancer, the STEAP family, but also the KLK2 target is a promising target for immunotherapy using T-cell engagers as well. One of the really nice things about the HK-2/KLK2 target for bi-specific antibodies is that the toxicity profile seems to be so favorable. I mean, really this is an easy drug to give. It has a minimum amount of CRS.

It's a very friendly drug from a patient perspective, which is an important thing in the field of T-cell engagers, and it does look like it has real drug activity. So I think many of us in the prostate cancer world are pretty excited about this possibility, because one of the intimidating aspects of T-cell engagers is the autoimmune and CRS phenomena that can be seen.

But this particular T-cell engager really has what looks like, at least in preliminary form, a very nice tox to efficacy ratio, which makes it a patient-friendly and clinician-friendly active therapy that's being investigated now.

Oliver Sartor: Right. Well, thank you, Mike. We're going to need to wrap up, but want to say thank you for covering KLK2 as a target, the concept of radiopharmaceuticals, covering a little bit about imaging, adaptive dosing, and also bispecifics concentrating on KLK2. So thank you very much. Mike Morris, chief of Prostate Cancer at Memorial Sloan Kettering. Thanks for being here today. Mike.

Michael Morris: Thanks so much for inviting me, Oliver. I really appreciate the opportunity.