Charles Ryan: Hello from APCCC 2019. I'm delighted to be joined by Oliver Sartor. Welcome, Oliver. An old friend of mine from many years, many conversations here and today we're going to talk about the VISION trial, which is a really interesting new approach to advanced prostate cancer. You're one of the co-PIs of the study. Tell us a little bit about the design of the study and what it hopes to achieve.

Oliver Sartor: First of all, let's talk about the agent that's going to be tested. And it's called PSMA-617 which is the name of the little ligand molecule that does the bonding to PSMA, and it's bound to Lutetium-177. And what happens there is the radionuclide, it's the beta emitter, is going to be going to those PSMA positive cells and deliver the radioactivity in a pretty precise fashion actually.

And so we have some preliminary data from Germany and others in Australia that demonstrate that it has some activity and it went into Phase III, and the Phase III is for patients who had previously failed abiraterone or enzalutamide and a taxane, and then the randomization is everybody gets a standard of care which is anything but chemotherapy basically, and plus or minus the PSMA Lutetium-177. And co-primary endpoints PFS and OS, and sort of the good news is it's about to complete accrual ahead of schedule I might add.

Charles Ryan: So it's an exciting agent. There's been relatively little experience with it in the United States, but lutetium has been used in Australia and Germany for a few years. I think they're... In those places it continues to evolve in terms of how it can be used in this disease, but if this is a positive study, as we hope it will be, how would we integrate this treatment into our management of patients?

Oliver Sartor: First of all, the FDA would approve in the context of the inclusion criteria of the trial. I mean that always occurs, and this will be kind of a post-abi/enza and post-taxane in the beginning. Now there are other trials that are designed to bring it upfront. In fact, it's all the way upfront. But that said, the initial change in practice will be for those individuals who failed where the novel anti-angiogenic abiraterone and a taxane. And then now you're going to have a new choice.

Charles Ryan: Is that the optimal biological space where we know that PSMA expression is the, is key in that setting?

Oliver Sartor: It may not be. Good question. And it turns out that when we looked at optimal biology, we might think the PSMA expression might actually be higher earlier. And there's more heterogeneity as the disease advances. And you end up with more PSMA negative disease as the disease gets very advanced.

So what we did was to use a PSMA scan and this one called PSMA-11 with Gallium-68 in order to find out where the cancer was and did it have uptake. So the inclusion criteria actually specifies if there'll be uptake on a PSMA scan. And that's how we chose the patients, and by the way, about almost 90% of the patients are eligible. But of course, we're excluding about 10%.

Charles Ryan: I see. So for those who are not familiar with this mechanism of action and this type of therapy, tell us about the logistics of how this is given. Is this given an infusion suite, radio... nuclear medicine? How would people integrate this into their hospital or their clinic?

Oliver Sartor: Yeah, great question. And first of all, it has to be administered by somebody whose licensed for radionuclides and typically that's either going to be nuclear medicine or possibly radiation oncology.

Now it's a low-energy beta, so you actually don't have to have a lot of protection. You don't need a lead [one 00:03:34] room. It's not like iodine. So the logistics of in and out are pretty easy. We've been able to get patients out within about two hours. We do monitor the radioactivity and ensure that it reaches a threshold that's commensurate with our local radiation safety program. But as it turns out, it's pretty easy to administer but must be administered by somebody licensed for the product.

Charles Ryan: Is the patient... So the patient is not radioactive when he leaves the clinical space?

Oliver Sartor: He's minimally radioactive. He's still going to have some precautions. Don't sleep next to the spouse, don't have the grandkids bumping up and down on the lap. But regardless, it's a pretty low level of activity. Pretty similar just to semarium. If you remember samarium it's a relatively low energy beta, so it doesn't really come out and cause... If I were radioactive post-lutetium, I wouldn't be getting you at all at this distance.

Charles Ryan: I see. Low energy beta, you said?

Oliver Sartor: Yeah.

Charles Ryan: Explain the difference between alpha, beta for those who are maybe used to giving radium-223 for example, how is this different?

Oliver Sartor: Yeah, so radium is an alpha emitter and that's two protons, two neutrons about particle size. It's big. And betas are basically electrons. And it turns out that they're much, much, much lower energy than the alphas.

But you end up with this crossfire. And what happens is when you deposit multiple little molecules in and around the cell, you can have these beta particles kind of firing off in a crossfire fashion. So the good news is you can have heterogeneity at the PSMA expression level within a tumor and still kill the tumor. Every cell does not have to be PSMA positive. It can kill neighboring cells.

Charles Ryan: So you can have a positive collateral damage.

Oliver Sartor: Absolutely.

Charles Ryan: But, we know we've... You and I have spoken many times about radium and samarium and radioisotopes. You've been studying this space for a long time. What should we be concerned about, if anything, with regards to that beta issue and the 617, the lutetium I should say, and toxicity in the marrow. What do we know? What are we expecting to see from the study?

Oliver Sartor: Yeah, so there's a little bit of toxicity in an unexpected place, and that's the salivary glands. For reasons that aren't completely clear there's PSMA uptake in the salivary glands, and you can get some dry mouth. And typically it's not too bad. It's excreted in the kidney as a small molecule with some uptake, but it turns out that so far the kidney has not been a dose-limiting organ.

If you end up with a high volume, like a super scan on the bone, you know there's more susceptibility to marrow damage. But the typical patient who may have, say, 8 to 20 lesions is not really that susceptible to-

Charles Ryan: And is the dose based on the number of lesions or?

Oliver Sartor: No, the dose is based on the kilograms and there are those who would argue that that's not optimal by the way, and that they ought to be doing sort of a dissymmetry approach. But the logistics of dissymmetry are quite complex and then you actually don't know what you're going to give the patient until you've already given it to the patient and measured the distribution. So it's a fixed dose and currently, there are four scheduled doses and if there's clinical benefit and the clinician who's administering the drug believes that there would be two additional cycles would provide more benefit, you can do that too.

Charles Ryan: So it's every four weeks at four...

Oliver Sartor: No, no, it's every six weeks.

Charles Ryan: Sorry, every six weeks. Okay.

Oliver Sartor: Yeah, yeah. It's every six weeks. Four cycles with two additional cycles being optional.

Charles Ryan: Okay, okay. So for those who are familiar with radium, it's not that dissimilar in terms of how it's being given. It's a nuclear medicine every six weeks.

Oliver Sartor: Yeah, intravenous infusion. Short-

Charles Ryan: discreet number of cycles, that kind of thing.

Oliver Sartor: Yep.

Charles Ryan: Okay. Very good. And one key differentiator with the VISION trial, this is not really a study based on the presence or absence of pain as the radium was, is that correct?

Oliver Sartor: Correct. It doesn't specify as symptomatic. The specifications for the prior treatments that I mentioned. Some evidence of progression after those prior treatments and then there has to be uptake on the PSMA scan.

Charles Ryan: Right, and just to make sure... Just to contrast it with radium again, is that that was a bone-targeted therapy for the most part, for the whole part I should say. But in lutetium we are, we can target visceral disease, we can target nodal disease. It's just about the PSMA expression-

Oliver Sartor: Wherever the PSMA expression is present, you can target. It does very, very well in nodal disease. A little bit of preliminary data that visceral disease spike in the liver may not be quite as responsive, but of course, when is liver disease more responsive? So those are always bad factors.

Charles Ryan: Right. Well, it's an exciting new agent and it's great to see a Phase III trial with all of the benefits that that can bring near the completion of accrual, and we'll look forward to hearing that data from you and your colleagues on the study in the coming years. So congratulations again. Great talking to you.

Oliver Sartor: Thank you. Thanks, Chuck.