Oliver Sartor: Hi, I am Dr. Oliver Sartor with UroToday. Really a pleasure for me to be able to have Karen Autio from Memorial Sloan Kettering, GU medical oncologist, be with us. I think we've all heard about pasritamig by now. Pasritamig is really a very cool way to approach it, and it's got some unusual dosing strategy and some unusual work that's gone into the behind-the-scenes effort to bring it into "drug-dom". And Karen is going to help us understand how we've arrived at the certain dosing that we're using today. So Karen, help us understand T-cell subtypes and dosing with pasritamig.

Karen Autio: Thanks so much for having me, Oliver. I'm just going to go ahead and share my slide so we can talk through it together. So as we know, KLK2 expression is highly expressed in prostate cancer from early stages of disease through castration resistance, and we previously presented results of pasritamig at ASCO in this past June to look at the efficacy of pasritamig. And in that trial, we also evaluated step-up dosing to reduce the risk of cytokine release syndrome. We looked at both subcutaneous and IV dosing. We selected IV dosing because it improved drug exposure, allowed us to get to higher drug concentrations, as well as avoid the injection site reactions that were associated with sub-Q dosing.

As part of the phase 1, we looked at several different dosing intervals. And ultimately, we settled on Q6-week dosing, which really optimized the drug concentrations and helped mitigate T-cell exhaustion. And that's the focus of what we'll chat about today more so. The recommended phase 2 dose for pasritamig uses two IV step-up dosing on day one and day eight, and then the target dose is given on day 15, and then Q6-weeks thereafter. So during the phase 1 clinical trial, a really interesting thing happened, and that is in two of the dose-escalation cohorts that used actually multiple weekly target doses, and then an increased interval. There was this subset of patients that actually experienced rising PSAs during the weekly dosing, and then this dramatic fall in PSA when the dosing interval was increased. So that really piqued our interest to try to understand the immune impact alongside efficacy of these different dosing strategies and why Q6-week dosing was most optimal.

The other thing we learned in the phase 1 clinical trial is that Q6-week dosing was associated with higher PSA50 responses when compared to Q3-week dosing using the same target dose. We hypothesized that increasing the dosing interval may actually lead to less terminal T-cell exhaustion and less activation-induced T-cell death. So just to walk through this figure of a simplified version of an immune response, a naïve T-cell, upon stimulation, can become an effector T-cell, is capable of a successful antitumor response and then antigen clearance. And then memory T-cells that are specific for that antigen are maintained by self-renewal. Now, if you have a naïve T-cell that undergoes chronic antigen exposure, which is the case for cancer, these cells can express TCF-1 or T-cell factor 1. And TCF-1-positive CD69-positive T-cells represent what's called a progenitor-exhausted T-cell.

These cells are capable of being programmable with stimulation and becoming an effector T-cell, and then a memory T-cell. And these cells may be stimulated or activated, I should say, by a T-cell engager like pasritamig. If, however, the progenitor-exhausted T-cell undergoes continuous stimulation, it will travel down this path of terminal exhaustion that leads to loss of proliferative potential and really no effector function. In addition, too much stimulation can then turn into activation-induced T-cell death. So that's a little bit of a simplified version of the background on T-cell exhaustion that may tie into dosing frequency. So in the phase 1 trial, what we did is we collected PBMCs from patients at baseline and then on treatment across all these different dosing groups. We selected samples from 27 patients and then grouped those samples by dose interval, either Q1-week dosing, Q3-week or Q6-week. And then we performed flow cytometry to look at markers of T-cell exhaustion.

What we found is that with the Q6-week dosing, these patients had more of these programmable progenitor T-cells, compared to those that were receiving Q1-week and Q3-week dosing. We also saw increased expression of CD69, which is an early activation marker associated with the ability of a T-cell to move from the lymphoid tissue into the circulation. Then we also identified that there was more AICD, more activation-induced T-cell death, in those patients that were receiving the Q1-week and Q3-week dosing compared to the Q6-week dosing group. So putting that all together, all of these translational efforts really do support the mechanism of action of pasritamig and the recommended phase 2 dose, which uses a target dose of 300 milligrams IV Q6-week. This Q6-week dosing appears not over-activate the T-cells and leads to less activation-induced T-cell death.

So importantly, Q6-week dosing seems to maintain this stem-like CD8 T-cell population that's capable of differentiating into an effector T-cell. I think importantly for our patients, the Q6-week dosing also certainly reduces clinic visits for our patients and has no impact on safety. So it doesn't impact the CRS profile of this agent. More broadly, I think what this research highlights is that the mechanism of action of T-cell engagers is really different from our other prostate cancer therapy. So in phase 1, when we're doing optimal dose optimization, it's really important that we include these immune parameters alongside pharmacokinetics and drug exposure. We're excited moving forward with further translational efforts that are looking at immune fitness and response and resistance. And as you know, the pasritamig is now being evaluated in a phase 3 registrational trial.

Oliver Sartor: Karen, that was really beautiful, and thank you for that explanation. I am not a T-cell expert. In fact, I'm anything but. So I've always struggled to understand the T-cell subsets and how they might play into the actual dosing and the actual translational effects on patients. And that's a really nice explanation. And it's interesting, this was an empirical finding. This was not a moment in which people said, "Oh, this is how we need to do it." This was noticing that the early weekly was not an optimal dosing. So help me understand a little bit how that works. Because J&J is a big company, and they get a big trial going. How do you pivot from one dosing scheme to another in the middle of a trial, where you don't anticipate that the Q6-weeks is really where you want to end up?

Karen Autio: So yeah, it was certainly paying attention, and folks at J&J and investigators paying attention to where the data was leading. With the weekly dosing, it was sub-Q, so the Q3-week had already shifted into the IV. Now, that particular anecdote that I showed on the slide of the patient who was on Q-week dosing and then dropped to Q3 and then Q6, one of the really fascinating things is that patient, it appeared as though they may be progressing. The PSA was rising, the alk phos was rising. They were supposed to be dosed at Q3. The investigator held the drug, the PSA had dropped, dropped again at Q6-week. And that, interestingly, was one of the first anecdotes that got everyone thinking, "Well, look. If the PSA dropped at Q3-week, how much can we stretch this out? Can this actually go to Q6-week dosing?" The PK profile supported it.

The toxicity profile was so low it also, I think, helped to support. There's always a concern if you stretch out the dosing interval too much, the cells won't be primed and that you'll have to redo the step-up dosing. But you're right, Oliver. At the end of the day, it was a bit of a pivot, and an important one in the phase 1 portion, to say, "Let's go from Q3 to Q6 and see where this leads us."

Oliver Sartor: No, I'm really seeing that in admiration because a lot of companies will start out, they have a plan. And the pivoting is really problematic, particularly as you're going through a multi-institutional phase 1. But in this particular case, paying attention allows you to probably come up with a proper dosing scheme, as compared to just bulling ahead and following the plan. So this is really interesting to me to be able to pivot in a multi-institutional phase 1 with a big company to probably get to the right spot. So I really love that. All right, I got to ask another question. So I, again, am not a T-cell expert. In fact, as I said, anything but. You're giving these large doses of steroids. I always thought that steroids was going to blunt the immune system and really just abrogate the effects. Yet, here you are and I think you're probably getting 16 milligrams of the dexamethasone, which is a whopping dose. Why doesn't that inhibit these T-cells from doing their work? Is it affecting something else? Why is my teaching wrong? Help educate me.

Karen Autio: Yeah, so I think that first off, the steroid dosing has to be in part in context of we know that steroids help prevent CRS. We need them for that purpose. They're also not for long-term use. So meaning it's the two step-up doses and the target dose that we need the steroid for. After that, investigators were allowed to discontinue the steroids and the majority did. And response to T-cell engagers is not just something that has to happen in the first month. These are long-term drugs. So I think of it as it's a balance. We need the steroid early on to mitigate the CRS. It's clearly not impacting our T-cells to the point that they can't be activated. They certainly are. And then it's not a long-term steroid use. It's a short-term steroid use. Maybe if we had to use steroids for months and months, this would be a different story, but we don't. It's just early on. It's the first day one, day eight, day 15. Then you're done with your steroids.

Oliver Sartor: Okay. Yeah, thank you. It seems like such a blunt instrument, but again, I'm not smart enough to know what might be a more precise instrument. But the truth is it works. One of the beautiful things about pasritamig is it is all outpatient dosing, you go home two hours later. Unlike, I'm going to say X, Y, and Z T-cell engager, where you end up putting people in the hospital and more, that this is really a step forward. So the outpatient dosing, combined with the activity, make it special. But there are other things that are in the works, and I want to get your take on this. There's also some PSMA-by-CD28 T-cell engagement that is ongoing in the background. Help us understand how that might feed into the pasritamig, and could that augment the effects that we're seeing now? So help me go down that CD28 pathway.

Karen Autio: So potentially CD28 could be an important combination partner. And I think a lot of what we're learning in the monotherapy trials of pasritamig, as well as some of the other combination trials, can help scientifically guide us as to whether or not that's going to be a good strategy. With PSMA, any sort of combination partner that will use a PSMA target, the toxicity profile may certainly differ. Because for KLK2, it's such limited expression. That's why we think we're getting such little CRS. PSMA-overlapping off-target effects that may come into play, that may make our toxicity profile for combination therapies more challenging. Whether or not PSMA and KLK2 ... They're both fairly highly expressed in prostate cancer, so whether or not a strategy that uses two targets that are oftentimes co-expressed is going to be the right strategy, I'm not sure. But we'll learn more as we do more of these translational works, I think, looking at pasritamig monotherapy.

Oliver Sartor: Well, and the cool thing is you'll pivot if it doesn't turn out to be what you initially presumed. So again, that's a bit of a heads-up. So Karen, thank you very much for the opportunity to understand more about the dosing strategy and schema, and congratulations on the successful pivot. Right now, we have a phase 3 trial called the COMPASS trial. Tell us a little bit about COMPASS, who's involved, what kind of endpoints, what are they looking at in terms of the trial design?

Karen Autio: So the COMPASS trial is a phase 3 international registrational trial. This is one that is for our patients who have received, really, all lines of treatments that are available. So ARPIs, chemotherapy, radioligand therapies, if available. And this clinical trial will be randomizing patients to effectively pasritamig versus best supportive care. It's a placebo-controlled trial, which again, can be done, given the low toxicity profile of this agent. So this is, I think, a wonderful opportunity for our patients that unfortunately are out of therapy options at this time. It's open and accruing. Pasritamig does have fast-track approval with the FDA now as well.

Oliver Sartor: Thank you very much, Karen. I want to thank you for taking us through dosing strategy, T-cell exhaustion, pivoting in phase 1 to get to the right place, and now, actually in a phase 3 registrational trial. So we actually covered a lot of territory in a pretty short period of time. Thank you for explaining it to our audience. Thank you for doing what you do.

Karen Autio: Thank you so much for having me.