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Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm here with UroToday. And a real pleasure to be able to welcome Ken Herrmann. I think Ken Herrmann is known to almost everybody in the theranostics field. He's the Chairman of the Department of Nuclear Medicine at the University Hospital Essen, Essen, Germany. And Ken, are you going to be talking to us about some tumor dosimetry? A really interesting substudy from the VISION trial. So I'd love to hear your perspective on this.

Ken Herrmann: Thank you, Oliver. Indeed, this is a presentation from EANM 2024. And it's obviously on behalf of the VISION steering committee and the VISION substudy investigators. And just to put it into perspective very quickly, a reminder. There was a substudy initially, including 30 patients, who were not randomized. They were treated according to the VISION therapy arm and receiving lutetium PSMA. And the primary idea was actually to find out, how is the safety profile? And the 29 patients were actually back then successfully analyzed. And we know very well from the publication in the Journal of Nuclear Medicine that the safety profile was very good and very low radiotoxicity in the organs at risk.

In addition to this, we have previously presented the tumor-absorbed dose in cycle number one. And you might remember—and this is a slide summarizing very quickly the corresponding tumor doses. And as you can see, it's around 6.5 gray per gigabecquerel in cycle number one for all lesions, a little bit less, 5.4 gray per gigabecquerel, in the bone lesions, and a little bit higher, 9.7 gray per gigabecquerel, in the lymphatic lesions. And this is very much actually in line with previously published ranges.

The idea of this subanalysis now was actually to look at how this dose in the tumor changes over the different cycles. Just as a reminder, we performed, in cycle one, a quite extensive dosimetry—four time points performing abdominal SPECT scans. Then in cycle two to six, we only performed one SPECT, which was then done in 36 to 48 hours.

Regarding the statistics, very quickly, we looked at the PET/CT in cycle number one, and in cycles two to six we used the CT images to determine the tumor volumes. And all the statistics were actually derived from the SPECT images. And very quickly showing you the results—and I think this is quite interesting. We looked, first of all, at a total of 60 different tumors in 18 patients. And also important to mention that around 75% to 85% of the tumors were in bone, only 15% to 25% of them in lymphatic tissue.

And when we look now at the corresponding results, we see very nicely that overall, the initial absorbed dose per unit activity was 5.2 gray per gigabecquerel, then decreased constantly to 2.5 at cycle number two. And you see this continued down to actually only 1 gray per gigabecquerel injected activity at cycle number six.

Also interesting to see that this phenomenon of decreasing doses was the same for both bone lesions as well as for lymphatic lesions. You see here the decrease was actually a little bit more steep when we look at the bone lesions. But again, we have more bone lesions than lymphatic lesions. The overall trend is pretty clear that we get a much higher dose per injected activity at the first site compared to later cycles.

The number of patients changed over different cycles, and that's why we actually looked at a subpopulation where we had measurements for all six cycles, just to be sure that we don't have any error there and selection bias. In the patients where we had data available for all six cycles, you can see the same trend. There's a decrease in the tumor-absorbed dose observed across all six cycles, going down from 4.0 gray per gigabecquerel down to only 1 gray per gigabecquerel at cycle number six.

Now, this is a lot of numbers, and just to visualize this a little bit better, as it's here, you see now the mean tumor-absorbed dose per cycle. You need to watch out that the y-axis in this case is a logarithmic scale. But what we see very nicely is, overall, the trend at cycle number one—we get a quite high dose per injected activity, which decreases over the different cycles.

And I think a very interesting information is—and this is in line also with previous reports in smaller groups and retrospective smaller groups—is that in cycle number one and two, actually, the dose we achieve accounts for around 60% of the overall cumulative absorbed dose if patients undergo six cycles of therapy. I think this is quite interesting information.

So, in summary, just to put this all together very quickly, we have prospectively shown in 18 patients with a total of 60 lesions that the absorbed dose per injected activity is going down from cycle one to cycle six. This is very much consistent with previous literature. And of course—and this is, I think, something we're going to discuss about—what is the consequence? What do we need to learn from this? But my personal take-home message from this is that we need to try to hit the tumor as hard as possible early on because then, we get quite a lot of tumor dose for the injected activity.

Oliver Sartor: Thank you, Ken. I really appreciate your covering that material. I think it has implications. But I want to ask you about how you might apply it. So one of the things that I made a note of is that about 61% of the absorbed dose is actually in the first two cycles. If you take this information into account, would this alter some of your future proposals about how this agent might be dosed? It's a very provocative question, but I'd love to hear your comment.

Ken Herrmann: No, it's an excellent question. Right now, we sometimes think about, how can we evolve in real life in therapy? Instead of giving six cycles of the same activity, we sometimes think about two with a high activity and then almost like a maintenance treatment. Technically, you would say, when you look just at the tumor dose right now, it's exactly what we did—or in the current fixed activity, if you look at the tumor doses, you have two high tumor doses, and then it's more maintenance dose.

So I think this is something we should look closer into, really now in the future redesigning this by giving two cycles of very high activity, probably much higher than what we give currently, and then maintain the activity at a lower level. And then, of course, we need to look at how this actually then implies, really, on the tumor dose. But right now, I think this is something which should be more and more encouraged when we see what was presented in Hamburg.

Oliver Sartor: Interesting. I'm sure you're aware that Scott Tagawa had actually dosed at a high dose in the beginning and is showing some pretty good results in follow-up. Now, he didn't give a maintenance; he just gave 11.1 gigabecquerels every two weeks times two, or just two doses total, and then that was done. Is something that extreme appropriate to consider, or do you think we need to really step into this in a little more dose schedule–controlled fashion?

Ken Herrmann: I mean, Scott's data is absolutely mind-blowing for two reasons. He's not only looking at giving higher activities, like the 11.1, but he's also—with the two-week interval—we also think about maybe we can actually decrease the side effects because we need a certain time, and that's where the six weeks come from. Why do we dose initially in VISION every six weeks?

And here, the idea is if you dose them two weeks apart—or Louis Emmett is doing a week apart—we might get more activity into the tumor and get less damage per achieved dose in the tumor. And the big question is if we think about this, really making a high impact early on and then getting certain maintenance, it's exactly what we need to talk about. Maybe not doing two cycles, like we discussed, six weeks apart, but maybe really two cycles one or two weeks apart, then a certain time for the bone marrow to recover, and then a certain maintenance dose.

In the end, you're absolutely right. We don't know. But I think the data we have seen is absolutely encouraging that we should look closer. We also know that we have a long way to go. VISION was beautiful data. But still, more than 50% of the patients didn't show a PSA 50 decrease. So there's a lot to win.

And we now see a couple of different angles. And I think playing around with the dosing—either two high activities early on, maybe even within only one or two weeks, and then a certain maintenance, or then maybe nothing and just wait until the PSA increases again—these are exactly the things we're going to see more and more in the future. And I personally believe that this is where we can probably tweak out even more efficacy without more toxicity for PSMA radioligand therapy.

Oliver Sartor: One of the other interesting observations here was a little bit of a distinction between the lymph nodes and the bone. And I wanted to drill down on that a little bit. It appeared as though the lymph nodes were actually having a little more absorbed dose relative to the bone. Now, is that some sort of artifact of the size of the lesion, the multiplicity of the lesions? Or do you think we're delivering more dose to the lymph nodes? Let's talk about the first dose initially, and then we'll talk about the sustained doses a little bit later.

Ken Herrmann: Again, very good question for a couple of reasons. So first of all, we know that, usually, patients with lymph node metastases seem to respond better than if patients have only bone disease. Now, what is the reason for that? Is it a different biology, or is it also because we have a certain measurement artifact? I think it's probably both.

On one hand, it's maybe really a different biology. Second thing is we probably also—for us, it's easier to delineate and measure the dose in the lymph node than, for example, in the bone. And I think both of them play a role. I definitely believe that, again, also for the future, we might treat patients in the future differently who have bone-only disease compared to patients who either have lymph node–only disease or have a mix of both.

On the other side—and this is quite interesting—when you look at the subanalysis of the 18 patients in the first cycle, the median was actually 5.2 gray per gigabecquerel for both lymph node and bone, which is a little bit distinct from what I showed you before for the overall analysis. So overall, it's difficult to tell if what we see is a real difference or not. I think it's probably also a certain artifact.

Oliver Sartor: Interesting. Now, I think in my own experience—and I'd like to ask you about your experience—I think patients are more likely to have progression in bone than they are to have progression in lymph nodes. Is that your experience as well?

Ken Herrmann: I fully agree with you. It's exactly what we see. Patients with bone metastases are the ones which are less likely to show a long-standing benefit from treatment than the ones which have predominantly lymph node disease.

Oliver Sartor: Now, we didn't really talk about it, but liver is yet even worse again. I call it the hierarchy of badness, and I talk—the liver’s the worst, then the bone, then the lymph nodes. Is that sort of an agreement that you would have?

Ken Herrmann: No, we have talked about this many times. The moment you have one liver metastasis, it completely changes the game biologically and prognosis-wise. So you're absolutely right. In this case, in the 29 patients, I think we didn't have a single patient with a liver met.

Oliver Sartor: Interesting. And just going back to one of the broader things, did you have any safety issues that could, in some way, be related to either low tumor absorption? I think about a little bit of a yin and a yang—the more tumor you have, the less normal tissue exposure you might have because the tumor is existing in this equilibrium with the normal tissues. Were there any hints that there were safety issues for either high- or low-volume patients?

Ken Herrmann: So not in this subgroup. I think this was overall really well tolerated. When you remember the publication in the Journal of Nuclear Medicine, where we published the normal organ doses, everything was along the lines of expectation. The effect you're talking about is, of course, a very interesting effect. The more tumor you have, the more radioactivity you deliver into the tumor, the less we see actually in the healthy tissues. This is something which has been shown quite a few times.

Now, the big question is, what do we learn from this, especially when we think about moving the therapy into earlier lines? And which I'm a big fan of, but of course it's still very exploratory and very research-driven in pre-docetaxel patients, because they obviously don't have much tumor, which means there is quite a lot of radioactivity that can go to normal organs. So this is something that we need to learn to understand, what are the implications of this?

Oliver Sartor: Yeah. Ken, this has really been a fascinating discussion. I think these data have implications for how we think about the entire field. And I could envision that there could be multiple studies with multiple agents that might actually show similar effects. So I'm thinking about this not only for PSMA-617 lutetium, but also extending to other agents as well. I really wanted to thank you for presenting this today. And before we sign off, I wonder if you might have any final comments or anything we've not covered that you'd like to cover?

Ken Herrmann: For me, the most exciting part of this is that we actually need to change the way we think. When we talk about dosimetry, right now, we always talk about normal organ dosimetry. I think it's important, but I think it's at least as important—maybe even more important—to talk about tumor dosimetry. And for me, as you know, we have much less data about tumor dosimetry than we have about normal organ dosimetry. And I think this is the exciting part. We now start to focus the attention on tumor dosimetry. This is early on, we have a lot to do, but I think it's a fantastic beginning.

Oliver Sartor: You know what, I want to ask you one more question because I meant to ask you this earlier. When it comes to the number of SPECT scans, I've seen highly variable numbers and timing after administering the lutetium dose. And I wonder if you just might comment about what you think is optimal and what you think is sufficient for SPECT scanning after administered dosing?

Ken Herrmann: So medical physics people usually want five or six, but this is completely unrealistic. I think what was shown here, I think for a study, is already a lot—four time points in cycle one and then reduction to one at later cycles. In the future, I think we should find a way to model with one time point only. Otherwise, we're going to make it very, very unrealistic to really roll this out everywhere.

It's one thing in Germany, where patients are stuck for two days in the hospital anyway, and we just have to put them on the scanner, which is unpleasant enough. Or if you want to go to Idaho, where the patient usually wants to leave the hospital after two or three hours. And I think that's why we need to be very reasonable. If we want to make this widely available, it has to be one time point only.

Oliver Sartor: Thank you, Ken. This is absolutely fascinating. Thank you for being here today—a really excellent overview of dosimetry, PSMA-617 lutetium, and implications for future dosing and safety. And I'll simply say UroToday really enjoyed having you.

Ken Herrmann: Thank you.