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Phillip Koo: Hello. My name is Phillip Koo from Banner MD Anderson Cancer Center in Phoenix, Arizona. I'd like to welcome you all to UroToday for a special feature that we have focusing on radioligand therapies in the clinic. And really focusing on the practical aspects of these therapies, especially since we now have the positive results from the VISION trial, which will hopefully lead to eventual FDA approval, which presents a lot of challenges for practices around the country and around the world with regards to how we operationalize this therapy, which is very new and different from what we are used to seeing in the clinic.

Welcome to UroToday for our special feature focusing on the practical aspects of starting a theranostics program. We are very fortunate to have with us today, Dr. Oliver Sartor, who is the Medical Director of the Tulane Cancer Center, and also the Assistant Dean of Oncology for Tulane. And also, Charlotte Manogue, who is the GU Program Manager at Tulane. So, I wanted to start off by talking about patient selection and obviously, theranostics is such a hot topic, and it's really the idea of combining the diagnostics with the therapies. So, how have you guys, together, really identified the patients best suited to undergo some of the trials and how do you foresee it is going to play out in the clinical setting once available?

Oliver Sartor: I think in some ways it's a little bit simpler than people may think. So first of all, we are going to have eligibility criteria. We're going to have inclusion, and we're going to have exclusion. So before we even think about doing scans, we, first of all, kind of run the traps. So whether or not somebody might have had the previous appropriate therapies, whether or not they have progressive disease, whether or not they have metastases on conventional imaging, all of which is required for the PSMA theranostics that we are currently using.

Now, once you go through that, then you've got to get the scan, and the scan, of course, we've been using is a PSMA PET. We've been using the PSMA-11 gallium 68 PET because that is where we've had the availability on this particular trial, the VISION trial. But we also have it available from an IND perspective that Charlotte put through the FDA. So, we've been using the PSMA-11 gallium 68 predominantly. And then, the reading criteria for who is and who is not eligible. I could go through that if you like. But the bottom line is, you choose the patients based on the scan and their prior therapies and other parameters such as platelet count, white count, et cetera, and it's not that hard. It's a little bit of a cookbook, but we open cookbooks every day.

Phillip Koo: So then, Charlotte, when a patient becomes eligible for one of these trials, have you had any concerns or resistance from the patient perspective about enrolling in one of these trials?

Charlotte Manogue: I don't think terribly much so. Probably, the biggest thing right now is travel and whether they can actually make it down here to Tulane on an every six-week basis. There is a financial burden to that if you live far away and some hesitancy to, kind of, come down all the time. Especially given COVID and everything else, but hopefully, that's not going to be any of a factor in the future where this is going to be in clinics across the country. And hopefully, COVID will go away soon.

Phillip Koo: Great. And I know for those patients coming from afar, you've taken extra steps to sort of make their trip as efficient as possible.

Charlotte Manogue: Yeah.

Phillip Koo: Can we talk a little bit about that?

Charlotte Manogue: So, getting their records ahead of time is extremely important. I take the first pass to, kind of, go through that cookbook as Dr. Sartor mentioned. If I'm, kind of, satisfied with the things that I know, I'll pass it along to the docs. Lots of people want the therapy, not everybody is qualified. So, some I can weed out right away. Others, we will kind of move to the next phase. Which is okay, they look eligible. Let's get them in to see one of the med oncs. If they're going to come from far away, I try to think about, ahead of time, when I have a scan available. So that I schedule them to see a medical oncologist in the same week or even on the same day that I have a scan available for them as well, and kind of hold spots for them in that regard.

And then after they have their scan, I like to block a little bit of time on Dr. Harris's schedule too. I'm always happy to give her time back to her, but it's much easier to block it out ahead of time. So that when they come down, they can kind of hit all three in either a day or a couple of days, and it makes their trip kind of worth it, I guess, in the first regard. And then, we're not having lots of extra trips for them.

Phillip Koo: That's great. That patient-centered focus and this idea of multidisciplinary clinics and care, I think it's so priceless.

So, Dr. Sartor, patients who undergo these radiopharmaceutical therapies, it's sort of a new paradigm where you have multiple therapies over an extended period of time and they see various physicians. How often do you like to see these patients during therapy and how do you, sort of in your mind, determine what your target dose is? I know in VISION, it was sort of four, up to six doses. How does that thinking occur and how do you imagine it will play out once clinically approved?

Oliver Sartor: Well, I'd like to see the patient before every dose and perhaps even a little bit more in advance than just a day. We have to make disease assessments. We have to worry about whether or not the patient is progressing. You can't just give the injections, and then think about the patient. The first thing is you pay attention to the patient and then you give the injections. So, a little bit like chemotherapy, if you're a medical oncologist, you don't just give chemotherapy without assessments. We look at counts, of course, and those are some of the parameters that are pretty easy to follow. What are the platelets? What are the neutrophils? That's easy, but what about the patient themselves? How's their pain control? To what degree are they responding or not responding? Are there additional therapies that might be warranted? We can use an external beam for instance.

Remember the way the VISION trial was constructed. It was standard of care plus the use of the radiopharmaceutical. And so, I may be handling the standard of care. What about their leuprolide acetate injections? What about the opportunity to use abiraterone or enzalutamide in combination? What about the bisphosphonates and bone protective agents? All that has to be dealt with, just like you deal with all your advanced patients. I think where you can make mistakes, are you just give the injection and forget about it. No, the patient is at the heart of the issue. Take care of the patient and give the injection in addition.

Phillip Koo: That's great.

Charlotte Manogue: I like for them to see him at four weeks so that I can order the dose and not wind up with a dose here that we can't use. So, if they see him at four weeks, he gives clearance to order the next dose. So then two weeks later, I'm getting them here for treatment.

Phillip Koo: Great. So a question that often comes up is, how do you monitor them? And you talked about a lot of different lab values and whatnot that you are checking. Imaging is often a question and I think some people think, "Oh, you will use gallium 68 PSMA during therapeutic monitoring." Some people say, "Oh, you should maybe do CT and bone scans." What is sort of your approach to the imaging follow-up of these patients.

Oliver Sartor: That's a really good question and I think it's evolutionary. So, as it turns out in the VISION trial, we were monitoring what we call radiographic progression-free survival and in accordance with the criteria that have been accepted by the FDA. Which is conventional imaging, so that will be a CAT scan, a bone scan, maybe an MRI, and that was set at regular intervals. Actually, I don't quite do that in practice and we are not really so much concerned about RPFS. We are concerned about patient benefits. Also, remember that there are health-related quality of life issues, and that could be formally assessed as we did in the trial or more informally assessed with, "How are you doing? How's your pain? How's your appetite? How's your activity?" We're monitoring performance status, et cetera.

So when we're going forth, we have not been using the PSMA PET as part of the integral ways to monitor the patients, but that was a restriction on the trial. Going forward, I could probably envision a day when that would occur, but we are not yet there from a regulatory perspective, from a reimbursement perspective. So, I think as we move forward with some kind of baby steps in this whole process, we're going to use conventional imaging, we're going to be using the PSMA PET at baseline. But later on, as the regulatory authority is allowing reimbursement, we will incorporate the PSMA PET in the assessments. To date, that has not been the case. But in the future, I think it will be.

Phillip Koo: Great. So, lutetium-177 can be imaged.

Oliver Sartor: Mm-hmm (affirmative).

Phillip Koo: What are your thoughts on the best way to incorporate that into their therapies? Are you routinely imaging them after their treatments? Do you see value in that moving forward?

Oliver Sartor: It's a great way to be able to look and see where the uptake is. And it's a little bit fascinating to patients when you can point out and say, "There is your tumor and it is being radiated because I see it being radiated." And, of course, we use SPECT scans, not PET scans when using lutetium-177, because we ended up with electromagnetic waves that are generated not from a positron, but rather, rather from a gamma. So, it turns out that we can image. We don't do it routinely, but it is kind of cool to do so. It turns out that it probably has a limited implementation in terms of routine patient care, but it is kind of fun to do and you can do dosimetry with SPECT as well. We haven't gone down that path, but I think there is a lot of cool studies, it can be done. We haven't done them routinely, however.

Phillip Koo: I agree. You said it before. You see it and you treat it. And that post-treatment imaging tells such a strong story.

Oliver Sartor: It's powerful.

Phillip Koo: Yeah.

Oliver Sartor: And it really, sort of, brings hope to the patient. We call it molecularly-targeted radiation. There are a whole bunch of different terms that you could use, theranostics or whatever. But to me, molecularly targeted radiation gets to the heart of the issue because there is a target, it's molecularly defined and we can see the target and we can see it being hit. And one of the cool things about the lutetium-177 when attached to the PSMA-617, it's internalized. So, it gets internalized into the cells. We image with the SPECT, and over a week later we see it. It's absolutely there in the tumor and that is how we know that it is reaching the target.

Phillip Koo: Absolutely, yeah. And you bring up the topic of dosimetry, which to me is exciting. But I think, obviously, we have to study that under some trials.

So, Charlotte, any last words that you have for the viewers out there with regards to the importance of what you are doing, and obviously as the GU Program Manager at Tulane, who is such a powerhouse when it comes to GU oncology.

Charlotte Manogue: Yeah.

Phillip Koo: You have opened up a lot of these trials here locally.

Charlotte Manogue: I think the biggest one is that it's not nearly as hard as you think it is to actually operationalize. But also, it's really lovely to see your patients, kind of, have the opportunity right now at, kind of, the end of their disease course to get a little bit of quality of life back that they might have lost over the past couple of treatment options and tolerate this therapy pretty well. I think that is the biggest thing for me.

Phillip Koo: Great. And Oliver, last comments.

Oliver Sartor: I'm grateful to have colleagues like Charlotte and Kendra Harris to be able to work with and we have a fantastic regulatory group as well. Sorry that [inaudible 00:11;26] Gaynell's not here. But we have people who work as a team. And if you want to be successful, that's what you need to do.

Phillip Koo: Absolutely. I think that is so well said. It really does take a village and it's been really a huge honor to meet the various team members and see how well people are working together to really elevate that level of care here. So, thank you so much for your time.

Charlotte Manogue: Thank you.

Oliver Sartor: Thank you.