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Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist, and an Associate Professor of Medicine at Northwestern University in Chicago. I am so excited to have here with me today, a good friend and colleague, Dr. Scott Tagawa, who is a Professor of Medicine at Weill Cornell at New York-Presbyterian in New York. Thank you so much for being here with me today.

Scott Tagawa: Thank you very much for the invitation.

Alicia Morgans: Wonderful. Scott, I wanted to talk with you about a phase One study that is being presented and being discussed at ASCO 2021. This is a study of actinium-225, a very specific agent though. I'd love to hear you tell us about the study, and of course, please explain to us a little more about this radio-pharmaceutical.

Scott Tagawa: Sure, I'd be happy to. I think most people by now are familiar with PSMA, as a cell surface antigen, that I refer to as a target. We can target that diagnostically, so as there are different PSMA pet agents, and we can target it therapeutically, generally speaking in three categories; with a radionuclide, i.e radiation, a drug, such as an antibody-drug conjugate, or with the immune system, that could be [CAR Ts 00:01:09] or it could be bi-specific.

The furthest developed have been the targeted radionuclide therapies. So I think a lot of people are familiar with Lutetium-177, which is a beta emitter. It happened to be gamma, so you can see it too. But we will focus on the therapeutic. A beta-emitter, compared to an alpha, is relatively weak but can penetrate through a number of different layers of cells, easily going millimeters, or sometimes centimeters, versus an alpha, ranging from, depending on which one and how many alpha emissions each one has, might be 3,000 to 4,000 times more potent, than a single beta radionuclide, but cannot penetrate nearly as far. So, differences in terms of the properties, I think are important.

And then we have different, what I call carrier molecules. Generally speaking, antibodies, which are large and small molecules, or ligand or peptides, which are small. People are familiar with these small molecules, which are small, they rapidly penetrate, getting into PSMA positive areas, which happen to be tumors and the prostate. As well as, roughly speaking, salivary glands, lacrimal glands, kidney, and small bowel. Antibodies have the advantage of circulating for a long time, so they will continue to target over days. And also the advantage of being too large to get into these PSMA positive areas, which are not tumors. They can not get into salivary glands, and kidneys, et cetera.

And they also have the disadvantage of the same thing, circulating for a long time, so it does include the bone marrow in terms of nonspecific uptake. This is a phase one trial, which had an initial dose-escalation portion that was presented last year, followed by a dose-expansion at a couple of sites at Weill Cornell, and Tulane. And we are presenting the overall combined results.

Alicia Morgans: Great. I'm assuming this is a really advanced metastatic castration-resistant prostate cancer population. How did you choose the patients? Was it all comers, or was there a specific group?

Scott Tagawa: So, the patients coming in were metastatic, castration-resistant, prostate cancer. Officially, they had to have received at least one of the modern potent AR pathway inhibitors. As It turned out, most had received two, and subjects had to have received chemotherapy for advanced prostate cancer, or have not been candidates or refused. And it turns out about two-thirds had received chemotherapy. We did not limit prior PSMA targeted radionuclide exposure so about 44% had received prior PSMA targeted radionuclides, generally speaking, lutetium-177. As we've done in most of our studies, over nearly a couple of decades, we performed PSMA imaging, but we did not use that for our inclusion criteria. Patients could have had very bright lesions, or nothing at all, and still get treated because we were still prospectively valuing that as a biomarker, and especially, it's not quite known for alpha.

Anyway, patients had PET imaging when they could, which was limited at Tulane, to the Weill Cornell patients who had PET imaging. Most turned out to be positive, but that was not an inclusion criterion. And the first part, from last year, was 22 patients were in dose escalation. I'm not getting into that in great detail, not sure that people want to know that in terms of dosing, but basically at the, [inauidble 00:04:53] sits with the second-highest level one subjects had a DLT, which was great for anemia, and thrombocytopenia. But zero out of six, had a DLT at the next highest dose level. We declared that the recommended phase two-dose, without hitting a true MTD and expanded there. A total of 16 patients, had what we would call the recommended phase two dose.

Alicia Morgans: Great. And so what are you reporting this year at ASCO with that expansion?

Scott Tagawa: We're reporting longer follow-up, as well as increased numbers in terms of PSA responses, CTC count changes, and adverse events. Amongst the 32 patients, about 69% had any PSA decline, and about 44% had at least a 50% PSA decline. And, again, these are patients heavily pre-treated, that might have had prior PSMA targeted therapy, that did get included just, or with a strong PSMA uptake.

We had 22 patients that had paired CellSearch CTC counts, the majority had control, either stable at zero, or decline if they were detectable, and with not much really mature follow-up, but more mature follow-up than last year. This was a single dose, by the way. After the single dose, the median progression-free survival for the entire population was five months approximately, with a median overall survival of 11 months.

In terms of adverse events. We really worry about myelosuppression.  Luckily there was not a lot of grade four hematologic toxicity. Three out of the 32 patients, about 9%, had grade four thrombocytopenia. One had anemia, and one had grade four neutropenia. It happens, but luckily not in the majority. Fatigue was one of the most common adverse events, mostly grade one and two. Although, four had grade three at any time. And then pain flares, and nausea, happened in a significant minority, meaning in the 40%, not quite hitting 50%.

Xerostomia, or dry mouth, is something that we look out for, and we worry about the salivary glands, and parotids, as highly radio-sensitive organs. We did see a grade one xerostomia. So 12 patients had grade one xerostomia, seven of those 12, had prior lutetium PSMA. I do think there can be some additive insult over time. But in summary with the single-dose, I would say that in an unselected patient population, it was reasonably well tolerated. And for a heavily pre-treated patient population, there was, interesting activity.

We're taking this forward.. this study is undergoing a fairly heavy biomarker analysis. Luckily we had some funding from PCF and DOD, and that is in progress. We've started several additional studies; one of them is giving a fractionated dose, so a dose intense, two-dose, day one, and day 15, single cycle, like we've done with lutetium and PSMA 617, as well as lutetium [inaudible 00:08:32], one that is more traditional, more moderate, lower dose, every six weeks. Up to four. We are doing a combination with a lutetium small molecule, so with lutetium PSMA [inaudible], and then a study that will start, hopefully in the next month or so, funded by the DOD, a combination with pembrolizumab in an AR singling inhibitor, that actually, it will be a randomized trial of an AR singling inhibitor, plus pembro, with or without, actinium J591, hopefully, to really stimulate the immune system.

Alicia Morgans: Wow. Well, great. It's exciting when we see these trials, that are able to move out of phase one, and continue to have these agents be investigated. And I would have to say that progression-free survival is pretty long for a single dose of, or, so it seems, in a heavily pre-treated population, that median PFS seemed very worth pursuing in terms of further work. And, clearly, you are in spades. Thank you so much for taking the time to share all of this with us. Do you have any closing thoughts, or just general comments on this work, to share with the audience?

Scott Tagawa: Well, it's a very exciting time for us that have been involved with PSMA targeting. I would say both diagnostics, as well as PSMA-targeted radioligand therapeutics, are really coming into prime time. I expect by the time ASCO rolls around, we will have another PET agent approved, and I expect that data from ASCO will lead to the first approval of a therapeutic.

Alicia Morgans: It is very exciting of course, for clinicians, but so exciting for patients and their families. Thank you for your continued efforts in moving the needle in this work, and in all of the work that you do. We appreciate what you do and your time today.

Scott Tagawa: Thank you very much.