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Alicia Morgans: Hi. I'm so excited to be here with Dr. Scott Tagawa, who's a professor of medicine at Weill Cornell Medicine. Thank you so much for being here with me today.

Scott Tagawa: Thanks for the invitation.

Alicia Morgans: Scott, you and your team had multiple presentations at ASCO 2023. One of those was a poster discussion that happened around some work that you and the team have done in a combination study of an alpha and a beta emitter. Can you tell me a little bit about that?

Scott Tagawa: Sure. So I think pretty much everyone has heard of PSMA now as a self-service target. There's a couple of points of background. So we can target PSMA using large antibodies or small molecules, and they both will wind up in PSMA positive tumor, but their circulation times and where else they land is a little bit different. Some antibodies are large so they circulate for a long time with some potential non-specific exposure but have multiple days to then target the tumor, which is maybe why they work in PSMA more than small molecules. And small molecules are small, so they rapidly diffuse to all PSMA positive sites and that can include salivary glands, lacrimal glands, kidneys, small intestine, et cetera. And then we can label those with different, what I call, effector molecules. So alphas are very potent, but a very short range, and betas, which are less potent, but a longer range.

So what we did was the phase one study essentially combining all those different factors. So an antibody radio label with the alpha emitter actinium 225 and PSMA I&T, which is one of the more common generic small molecules, radiolabeled Lutetium 177, which I think most people are familiar with. And then did a phase one dose escalation study, basically where everyone got kind of standard fixed doses of Lutetium PSMA I&T, using the splash regimen, which is 6.8  becquerel every eight weeks, and then three different cohorts of different radioactivity doses of actinium with J591.

Alicia Morgans: Wonderful. And so obviously this is a phase one study, so you're not really looking for efficacy and durability. Sometimes we find these signals, but really, the purpose of these trials are to help us understand the safety profile of these agents. So tell me a little bit about what you found when you combined these two approaches.

Scott Tagawa: The one line answer was feasible and safe. So as kind of standard medical oncology dose escalation studies, we had a defined period of assessment of dose-limiting toxicity, which was eight weeks, or up to 11 weeks. We had relatively standard definitions of dose-limiting toxicity, so grade four heme toxicity, grade three non-heme toxicity. But we also insert in even grade one toxicity that precluded dosing on time of cycle two. So a delay by three weeks was another definition of DLT. And at the highest dose level, there was a grade two thrombocytopenia DLT and a grade three thrombocytopenia DLT. So it's a little bit weird why a grade two thrombocytopenia would be a DLT, but it was defined like that because it would've delayed the second cycle by three weeks. So that's what we found at the highest dose level. So the intermediate dose level is what we're calling the recommended phase two dose.

Alicia Morgans: Okay. And did you see any signs of early efficacy? I'm not sure if you really monitored PSA and those kinds of parameters.

Scott Tagawa: Looking at an imaginable waterfall plot. One went up, so 17 out of 18 went down, so PSA reduction of any percent in 17 out of 18, and 11 out of 18 or 61% had a PSA 50 in terms of 50% PSA reduction any time. We looked at circulating tumor cells as well. So different kind of cutoffs, but if you look at using cell search, the unfavorable, there were seven at the start and five converted to favorable, and overall, most had some sort of CTC conversion as well.

Alicia Morgans: Yeah, absolutely. That's wonderful. So any other findings? Anything else you were looking for? Any gestalt or thoughts about how to interpret your data?

Scott Tagawa: So I guess I really only mentioned the DLTs. There were, of course, other adverse events. Hard to tease out if it's more than expected from either single agents, but not really a lot of grade two or three or four adverse events. So there were three patients with grade two to three thrombocytopenia, but really, the half that had thrombocytopenia was grade one. Two thirds did have dry mouth, but really, virtually all of them was grade one and improved with time, as we kind of expect with these agents. And with the alpha, we were a little bit more, but it appears that it may be a little bit safer attached to the antibody rather than the small molecule.

I'm biased, but I think it does look interesting and I'm looking forward to phase two. Kind of a subtly of this is we were receiving the lutetium PSMA I&T from POINT Biopharma. They have recently partnered with Lantheus to hopefully get their drug approved. In that transition, the I&T's kind of went out the window, so we no longer have a supplier, so we're going to just do it our own because I&T, it's generic, but that is stalled us between phase one and phase two where we need to get an IND. But hopefully we can have tighter confidence intervals around efficacy in the phase two study.

Alicia Morgans: Okay. And so the goal is to have a phase two and to really continue this proof of concept with that, the recommended phase two dose that you've established in this phase two. And do you see this potentially being a study that hopefully launches within the next year or so? What do you think?

Scott Tagawa: You never really know. We've been generally successful with our INDs. I think we have six or seven different INDs. The FDA works with us pretty nicely as academic investigators, but of course, we never know. But people have done it before, so it should be ... our chemists are great so I don't think that's going to be a major problem. It's a funding issue, so we're looking for that.

So just to kind of step back, this concept essentially took a leap. It's testing potentially multiple questions at the same time. The antibody, small molecule combination, alpha beta combination. So if this is better than historic controls, hard to know, but if it is better either in terms of safety or efficacy, I'm not sure what the component is from the antibody or is it the alpha plus beta. But one thing I forgot to mention is that there is an interaction with the antibody and the small molecule, at least preclinically, where the small molecule binds PSMA, is internalized and then spit back out. If that small molecule is there just with the antibody, no alpha, just with the antibody alone, then the small molecule is retained inside the cell. And if it stays for longer, then there's higher reactivity. So it's a way of getting a higher dose to tumors without even adding that alpha.

So if it is better, I don't know if it's because of that or it's because of alpha ... As a doctor taking care of the patients or the patient potentially seeing benefit, I don't think that really matters. But we do have separate trials that are looking at that more precisely just with the unlabeled antibody.

Alicia Morgans: That's really fascinating. Well, certainly as that trial comes to fruition and as you ultimately hopefully launch that within some timeframe, you'll have to let us know. I just want to mention and acknowledge that every once in a while there's a patient of mine that needs an additional clinical trial. I know you at Cornell are doing some fantastic work and often have clinical trial opportunities for patients who want to engage in radiopharmaceutical work. And so I'm sure that that folks can reach out to you if they do want to refer a patient. But at least it's a resource for me. And now that it's on UroToday, I hope that it's a resource for many to get patients to your studies.

Scott Tagawa: Happy to talk to any of the doctors out there that have questions, or patients. We have a study email address, and people can reach out.

Alicia Morgans: Wonderful. So what's your final message on this work? And congratulations again to you and the team for getting this phase one not only off the ground, but to a wonderful poster discussion at ASCO.

Scott Tagawa: So I think there are lots of preclinical and clinical rationales due to this combination, but I do think that all combinations should be done in a prospective, carefully designed manner. So there are manuscripts that are out there that have combined alpha and beta, not saying on the same day, but have combined alpha and beta. And this is the first one to prospectively. So I say the totality of the data looks like it is feasible, including in a prospective trial.

Alicia Morgans: Wonderful. Well, thank you again so much for your expertise and for sharing your time today.

Scott Tagawa: Thank you very much for the invitation.