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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, Dr. Scott Tagawa, who's a good friend and colleague, and a Professor of Medicine and Urology at Weill Cornell Medicine, and an attending physician at New York-Presbyterian. Thank you so much for being here with me today.

Scott Tagawa: Thanks so much for the invitation.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about several of your ESMO presentations from 2021. Let's start with your focus on really having a dose escalation of lutetium PSMA to help us understand exactly how to best dose this drug. Now, of course, we have the VISION data that came out at ASCO earlier, and so we are very excited about anything related to Lutetium of course, but really I think this work is some of the first dose-finding and dosimetry work that's been done and reported. Can you tell us a little bit about what you studied?

Scott Tagawa: Sure. This is a study that actually was designed in 2016 and started in January, February 2017. The background is that there is a number of different small molecules against PSMA, most often radiolabeled with Lutetium-177 and most will give what I would call a moderate radioactivity dose every six to eight weeks. Not entirely imperiously, it's based on some dosimetry and expert opinion, but no true medical oncology dose escalation studies were ever done.

Another bit of background is that just with the mechanism of radiation, we know that repopulation is the mechanism of resistance. So as we are looking to cure someone with localized disease, we're not giving a dose, waiting a month, and giving another dose. We want to have that in a relatively dose intense fashion. And then we've been using lutetium with [inaudible 00:01:56] antibody for a long time and looked at a single dose and then came up with a fractionated dose schedule, which we kind of handed off to pharma. We took all that information together and said, "Okay, let's do a dose-escalation study and we like this fractionated dose regimen, which is dose intense from the antibody, and let's go forward with it." So, we did a phase 1 dose-escalation study followed by phase II at the recommended phase II dose.

Alicia Morgans: Tell us a little bit about that, and if you could, try to help us put this into context with the dose that was used in the VISION trial, just because I think for most of us, these are not doses that we are highly familiar with and it does help us to understand how you kind of wanted to do a more intense and maybe compressed treatment regimen that might be, like you said, one of these more intense, perhaps more effective ways of using the drug.

Scott Tagawa: Sure. I understand the confusion because there is different terminology, there are different units that are used, but I'd say kind of simply a dose of between five and eight up to nine, so five to nine, let's say gigabecquerel as a single dose of Lutetium-177 with a radiolabeled small molecule has been given.  7.4 gigabecquerel, which is a little bit on the higher side compared to 6.8 to 7, which was done before.  But 7.4 gigabecquerel or 200 millicurie is the dose that was used in VISION, and the other phase III trials that have started with that particular drug. So in our dose-escalation, we fractionated the dose. So half is given on day one and a half is given two weeks later on day 15. So we started with that dose, half-day one, half-day 15, and then went up from there. And basically, we went up to 22.2 gigabecquerel, so that's 11.1 times 2 within the two-week period, but the cycle is 22.2 gigabecquerel. And that is in comparison with a single dose of 7.4 in VISION.

Alicia Morgans: That's really interesting because when you do something like that, you might see that there are more adverse events or that it is more difficult for patients to tolerate. What did you find?

Scott Tagawa: So during the dose-escalation parts, it's important to say that the DLT assessment period was 12 weeks, so longer than sometimes we do with chemo and other drugs, but relatively short in terms of what we know can happen in the long run with radiation. So just a caveat that is there. But basically, there were no DLTs at any of the dose levels. I suspect that is because much of the excess dose is cleared fairly rapidly in the urine. That's number one. And then number two is PSMA, while not 100% selective for prostate cancer, the distribution is relatively selected and the non-profit cancer sites that have PSMA can handle that dose of, I can say that with confidence now, can handle that dose of Lutetium-177, at least, which is a relatively low energy beta. So I think there is some damage to some of the sites, so nausea in terms of the small bowel and dry mouth in terms of the salivary gland, but, just kind of minor damage. And then they recover.

Alicia Morgans: So really, really important. And what did you see then in terms of responses? It sounds like it was relatively well tolerated, really only those two doses. What did you see in terms of responses?

Scott Tagawa: Yeah, so the other, I think the important thing to put this into context, in this non-randomized trial, is the patient population. So we didn't require prior chemotherapy, but it generally was about six out of 10 had at least two potent air pathway inhibitors and chemotherapy. About three out of 10 also had radium and about three out of 10 had [inaudible 00:06:17] TIPT. But the other part in terms of extrapolating to other datasets is that we did not use PSMA selection. So patients all had some sort of PSMA imaging, but it was ignored in terms of patient selections. So, I think that if anything, the results are pretty good because there is a wide range of PSMA expressions. And when we did look at the PSMA expression, which did have an association with a positive outcome, we only looked at the hottest lesions. So we ignored discrepancies that are really enhanced looking at the therapy data where there is dual PSMA and FTG, but also described it in VISION looking at the CT portion, so basically soft tissue lesions that didn't have any significant uptick

Alicia Morgans: So agreed. That is really important. And I think it's important too, for us, as we think about the next steps, whether patients need to have this larger amount of PSMA positive disease, what percentage of their cancer cells can actually not be PSMA positive, but they could still have a benefit. We are still certainly working all of that out. So I'm glad that you clarified that. And I know that some of the outcomes that you looked at in this study, again, are single-arm and non-randomized, obviously because of that, they seemed similar actually to some of the results that we are seeing in VISION. Is that right?

Scott Tagawa: Yeah. Again, it's extrapolation, but a little more than half had at least a 50% PSA decline. Interestingly, the radiographic progression-free survival of 9.6 months, it's pretty on, I mean, it's a little bit longer, but pretty right on with VISION. And the OS is almost exactly right on at 15 months. So again, different patient populations. My hypothesis is that the dose-intense regimen makes up for the lack of PSMA selection. So some of those that have less PSMA expression because of the higher dose intensity, might have a higher chance of response. That is my hypothesis, but something is happening where we are able to compensate for that. Now, that being said, we know the vast majority of patients [inaudible 00:08:58] it's 19 out of 20 that have quote positive PSMA imaging, meaning at least one lesion that has a higher SUV than the liver. There's more with the discrepancy, but we do know that PSMA is there most of the time, even in this really heavily pretreated patient population.

Alicia Morgans: I think that's really important. And I love your thought that it might be that if a patient has a lower level of expression of PSMA, the higher dosing may actually kind of make up for that difference and provide some of the same disease control. It's certainly a good hypothesis. Is this something that you and the team are able to move forward with because certainly VISION is finished and, and other work is being done, but I'm not sure how much work is being done with changing frequencies of doses or changing dose? And so what are your thoughts in terms of the work that is being done or will be done to clarify some of that?

Scott Tagawa: So we started this with donors. There was no such thing as Endocyte at the time. It existed, but they didn't own this compound. So we purchased 617 from AVX and we purchased lutetium and created our own drug and did the phase I study basically. And then Endocyte came in and did support us. So they then provided the 617. We still bought the lutetium, but they provided the 617 as well as some support for the study. But anyway, this was really an academic study. As a cynic, I don't know that a drug company would say, four to six doses versus something that's the same with two doses. Do we want to go forward with that? So anyway, I think it's interesting. I do applaud Novartis for moving forward with additional studies.

I think it's important with earlier lines of therapy. I think that there may be a bigger bang for our buck. And as you know, we in the cooperative system are in discussions with ways to look at alternative or maybe individualized dosing of these things to either kind of maximize an individual's response or maintain a good outcome with maybe less exposure. So I think there are things that can be explored, I think it's a little bit more complicated with this, because if we are depending on insurance to pay for it, would they pay for a higher activity level? I'm guessing not, but who knows? But I do think that this regimen is interesting and going to another construct, there is a phase III with this, with the antibody. So Telix has launched phase III with a fractionated dose regimen. And we are also exploring it with an alpha.

Alicia Morgans: So really, really interesting. And I don't know, we never would know how different companies might think to invest in and pursue different regimens, but at least with radium, there was a study. I remember Cora Sternberg leading the way and presenting that where they gave a higher dose and they also gave a prolonged dose just to see if there were going to benefit. It seemed in that case like we somehow managed to find ourselves with the right dose and the right number of doses on the first go-round. But I kind of envisioned something like that perhaps happening, but good to know, at least that there is more work being done.

And do you want to mention, before we wrap up, the work that you are doing, the study that I think you are leading in metastatic hormone-sensitive patients?

Scott Tagawa: Sure. I mean, officially there's a steering committee, but a long history of the study, now a worldwide Novartis study called PSMAddition, which is looking at men with, I'm going to say the same thing in three ways because there is different terminology.  I guess, officially non castrates if you go by the working group or ASCO [inaudible 00:13:21] hormone-sensitive or castration sensitive. But looking at what I think is the most common standard of care, which is ADT plus an AR pathway inhibitor. And then randomized to the addition of hence the name of lutetium-PSMA-617 at the same 7.4 gigabecquerel times four to six as done in VISION. Unlike VISION, which had this dual primary endpoint of rPFS and OS, this is a simple primary endpoint, one primary endpoint only of rPFS. However, which I think is nice for volunteer subjects, is that there is crossover. So those that are on the control arm, which we know actually do pretty well compared to historical controls with ADT alone, will have the opportunity to get lutetium-PSMA-617 [inaudible 00:14:15] that's confirmed radiographic progression-free survival and there are a number of other interesting secondary endpoints.

Alicia Morgans: Well, thank you for sharing that because I do think that is going to be one of the blockbuster trials coming up, coming down the pipeline. And I want all of the listeners and patients who might be listening to be aware of that trial and see what you can do if you are interested if you fall into that category to think about getting to a site where you might be able to participate because especially with the crossover opportunity, I think that is going to be really a trial that is investigating a very important question, but does give an opportunity to patients to have access. So thank you so much for sharing this. I'd love to hear your final thoughts on the work that you've done with the different dose fractionation and where we go from here.

Scott Tagawa: Yeah. So I think that at least I have thought for a long time, that PSMA is a great target and now we know it's a great target, both diagnostically and therapeutically. And we have what we think is the first approval study. We shall see what the FDA may say, but now I think we have much more work to do figuring out a different regimen, which includes single agents or a combination as well as different patient populations that will optimally benefit. So I'm glad to be a part of some of that.

Alicia Morgans: Absolutely. I'm glad too. I really appreciate your continued efforts in this field of radiopharmaceuticals and really appreciate you taking the time to explain all of these things to us. Thank you so much.

Scott Tagawa: Sure. It was my pleasure.