Hi, my name is Scott Tagawa. I am a medical oncologist at Weill Cornell Medicine New York Presbyterian Hospital in New York. We presented results from a study from a PSMA-targeted radionuclide therapy, specifically actinium J591, for men with metastatic castration-resistant prostate cancer (mCRPC).

By way of background, I think most people are by now aware of what is PSMA, as in a cell surface protein or antigen with expression, and generally high levels of expression, on prostate cancer, particularly with increasing expression following metastasis, higher grade and hormonal therapy, with some expression in other areas of the body, such as the kidney, the small intestine, salivary, and lacrimal glands, and interestingly the neovasculature of solid tumors.

What some people may not be aware of is that we can target PSMA with antibodies which are large. They have a long circulation time, but they are also large enough to not be able to typically get into areas such as the kidneys, small intestine, salivary, and lacrimal glands.

Because of their long circulation time, whatever is attached to it has the potential to hit areas that are nonspecific, like the bone marrow. Then small molecules, such as PSMA-617, which we just heard about in the plenary session with the VISION study, rapidly diffuse to areas of PSMA expression, such as tumors.

Also the other areas, such as the kidneys, salivary, lacrimal glands, and the bowel. That is one important piece of background. I think people are aware of the difference between alpha and beta emitters.

This particular study used an alpha emitter, so just high level, very potent, but also very short-range. Wherever it gets to, based on the potency, is likely to be damaged or killed, but neighboring cells are less likely to be damaged or killed because of the short range.

Overall, we hypothesized that, by using a full-length antibody -- specifically, J591 -- to take a potent alpha emitter, we would be able to do this safely. We started a phase one dose escalation study. The dose escalation results were presented last year.

Briefly, we went up to the highest dose levels, the seventh dose level. At that dose level, zero out of six had dose-limiting toxicity. One in the previous dose level had dose-limiting toxicity, but overall, in those 22 dose escalation patients, we showed some safety.

At ASCO 2021, we have further follow-up of those 22 patients, plus an additional 10, so a total of 16 patients, treated in the expansion at the recommended phase two dose. To get in, patients had to have progressive disease despite a modern potent air pathway inhibitor.

As it turned out, almost 80 percent had two of them. Patients had to have chemotherapy or be ineligible or refuse chemotherapy. About two-thirds had had prior chemotherapy. We allowed prior radium as well as PSMA-targeted therapies, so about 44 percent had prior lutetium PSMA.

We included PSMA PET as part of the screening procedures, but the results were ignored, and the patients were treated, regardless of PSMA expression. What we found is that it was overall safe.

In addition to just the dose-limiting toxicities, with longer follow-up outside of the DLT assessment period, plus with longer follow-up, we do see a little bit more in the way of grade three and four toxicity than was reported with short-term follow-up last year.

Aside from hematologic toxicity, only four patients had any non-hematologic grade three toxicity. Four patients had temporary grade three fatigue. The other grade three and four events were limited to lab toxicities, which were generally mild suppression, which also was generally speaking temporary in nature.

In terms of low-grade toxicities, the majority did have at least some fatigue. There were pain flairs that we have seen with a number of different PSMA-targeted radionuclide therapies. There was some grade one nausea, and there was some grade one dystonia.

37 percent, or 12 out of the 32, had grade one dystonia. Of those, 7 of the 12 had prior exposure to lutetium PSMA. Exactly why that happened is unclear, but perhaps some of those tight junctions were broken down by prior PSMA-targeted radiation to the salivary glands.

Then, despite having a number that had prior PSMA-targeted radionuclide exposure that we did not select for PSMA expression, the majority did have some PSA decline -- about 69 percent -- with 44 percent having at least 50 percent PSA decline.

Of the subset that had cell search CTC counts, the majority had either declines or stability at zero. One had stability at two. The median PFS following a single dose of actinium J591 was five months. Overall, we concluded that PSMA-targeted alpha particle radiation using antibody J591 is safe.

There is some early preliminary evidence of activity, PSA declines, and CTC count declines. We are analyzing a number of exploratory corollary studies, such as further looking at imaging, but also immune and genomic biomarkers, as well as looking at patient-reported outcomes.

This first-in-human study that started in 2017 and then finished up at our two centers in New York and New Orleans had led to additional phase one and two studies that have either started or are starting in June 2021.

That includes fractionated dosing, so a dose-intense regimen which we have used with a number of different lutetium agents. Multiple dosing, so the more typical lower doses, spread out over time. Retreatment, so using this PSMA-targeted radionuclide approach in those that have already had PSMA-targeted radionuclide therapy.

A combination with using this antibody alpha, combining with a small molecule beta, specifically. Then a randomized trial in those with chemo-naïve metastatic CRPC, with pembrolizumab and ARC inhibitor, randomized to those two drugs alone, with or without actinium and J591 to see if we can generate subsequent immune response using radiation.

Rather than external beam radiation, using a PSMA-targeted alpha emitter.