Exploring the SPLASH Trial: PSMA I&T Lutetium-177 in Pre-Chemo Metastatic CRPC - Oliver Sartor

November 2, 2022

Alicia Morgans speaks with Oliver Sartor about the SPLASH trial and advances in radioligand therapy. The SPLASH trial involves PSMA I&T Lutetium-177 (renamed PNT2002) for pre-chemo, metastatic CRPC patients, with some differences in dose and schedule compared to PSMA 617. In the lead-in study involving 27 PSMA PET-selected patients, the initial PSA 50 response rate was 40%, and the radiographic response rate was 60% in a small group. The initial rPFS comes in at about a year, with a promising safety profile. Drs. Sartor and Morgans discuss the differences between PSMA I&T and PSMA 617, and expectations for the SPLASH trial. They also highlight the importance of competition in radioligand therapy and the anticipation for more options that can provide better access and choices for patients.


A. Oliver Sartor, MD, Professor of Medicine, Urology, and Radiology, Director Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi. I'm so excited to be at ESMO 2022 where I have the opportunity to speak with Professor Oliver Sartor of Tulane in the United States. Thank you so much for talking with me.

Oliver Sartor: Thank you, Alicia. Good to be here in Paris.

Alicia Morgans: It is great to be here. Really exciting to talk about radioligand therapy and advances in that part of our field. Today I wanted to talk with you about the SPLASH trial, which was presented here at ESMO 2022.

Oliver Sartor: Interesting trial. So first of all, SPLASH is going to involve another PSMA ligand called PSMA I&T, Lutetium-177. It's been sort of renamed PNT2002. They did a little changes to make stability different, but it's really PSMA I&T with Lutetium on it. In terms of what was presented here at ESMO, there's no randomized data. There was a lead-in that was required by the FDA. It's 27 patients, but they PSMA PET selected the patients. By the way, it's important to know this is not in the post-chemo setting. This is in a pre-chemo, metastatic CRPC setting. They actually did allow docetaxel if it were given for castrate-sensitive disease more than one year before the trials began. There's a smattering of patients with prior docetaxel, but the majority of these are metastatic castrate- resistant post-abi enzyme, kind of that post novel hormone space. PSMA PET, 85% of the patients qualified, and then a little run in.

Now the dose is a little different. It's a little bit lower than you get with PSMA 617, and the dosing is every eight weeks for a maximum of four doses. I say, why the difference? Could be that there's a little more renal exposure in this particular ligand, but at the same time, we know that this particular agent is safe. It's been given to many, many in the German setting. And what can we say about the initial results? Number one, it turns out that the PSA 50 response rate is about 40%. That's fairly similar to what was seen in VISION. We can also say that there was an objective response rate, radiographic response rate, of 60% in a small group. So only 10 out of the 27 actually had measurable disease, but of those, 60% actually had a CR or PR. So I thought that was pretty good.

And then if you look at the initial rPFS data, remember this is not very mature data, but it turns out the initial rPFS is going to come in at about a year. And so, safety profile, good, no really alarms in the safety profile. And this will now move on to the randomized phase. And the SPLASH trial, we'll use the two to one randomization and we'll use the PSMA I&T Lutetium-177, as compared to a second novel hormone in the post-abi enza space. And the primary endpoint is RPFs, and there's a crossover. So now the trial is underway, and of course, we got to wait results, but my understanding is accruing very well.

Alicia Morgans: Well, that's fantastic. Let's talk a little bit about the differences between this agent and Lutetium PSMA 617. Other than the schedule, and you mentioned the dose, what should we expect here from your perspective?

Oliver Sartor: I don't think we can expect a great deal of difference. If you look at the 617, it may have a little more favorable renal dosimetry, but there's a little bit of data that says the PSMA I&T may have a little better tumor binding. And the uptake seems to be pretty much close to the same. I think without a doubt, it's going to be an active agent. I think that the PSMA 617 every six week schedule is something we're familiar with from the VISION trial. And this will be q eight weeks. Some people are saying, "Gosh, do you get enough dose density," and things like that. The trial will tell. And in the end, we're going to figure out exactly what's going to be seen because we're going to have the data.

In terms of other differences, they're both carrying Lutetium. The dose is a tiny bit lower with the PSMA I&T, but where we are on the dose response curve, I might remind people who are listening that Scott Gajobo gave much higher doses than was given in the VISION trial with PSMA 617 Lutetium, and never encountered any DLTs. So where we are in the dose response curve, I think we're in a pretty sweet spot, and I think we'll just have to wait for the randomized phase three study to look at it. But the preliminary lead in data, I think is promising.

Alicia Morgans: That's really exciting. So from a patient perspective, do patients have the same restrictions that they have with Lutetium PSMA 617?

Oliver Sartor: It'll be essentially the same. So, the Lutetium is still going to be that beta emitter. You're still going to run almost a week half life, and they're going to be some controlled exposures you need to be aware of, and social distancing, et cetera. So I think it'll be pretty similar, but we're probably all aware, and I don't want to get into it too far, that some of the supply chain and other issues, with 617, I think competition can potentially make things better. And if we have a little bit more in terms of agents, then we have more in terms of agents and more options for patients are generally a favorable thing to have.

Alicia Morgans: Oh, absolutely. And I'm hopeful that having options will give access to folks at different places where there may be less access now. So from your perspective, when do we expect to get some of the first data on this SPLASH trial? I'm excited to hear about this lead in, but when do we expect that study?

Oliver Sartor: Yeah, so it's accruing quite well right now. I'm not able to give a definitive I class patient end date, but I'll simply say that there's enthusiasm for the trial. There's a two to one randomization for the Lutetium. In addition, there's a crossover. Those people in the control group with the primary endpoint, they can crossover, and people have been able to get patients enrolled. And there are a number of sites now rolling. And I'll say, PSMA I think will go well. I wonder if it might be possible to mention the PSMA 4, which is also in the pre-chemo, metastatic CRPC space. And accrual has been very, very robust. And I'll just simply say the endpoints will likely be reached it's going to be reached. I can't give you an exact timeline because it's an event driven analysis of course, but I think we're going to be hearing before too, too long.

Alicia Morgans: All of that is so exciting. And any opportunity to get therapies to patients that may prolong their lives, especially when the toxicity profile is pretty tolerable, is really, really important. So if you had to sum up where things are right now in radioligand therapy, and for agents that are actively being investigated in these larger phase III regulatory type trials, what would you say?

Oliver Sartor: So first of all, we have the VISION trial, and I don't need to cover that again. It's positive. We have an FDA approval. The next three trials are the PSMA4 trial with PSMA 617 Lutetium, and then we have two PSMA I&T trials, both with Lutetium. One is called SPLASH, and that one's moving forward quite quickly. The other is called ECLIPSE, and the ECLIPSE trial was also accruing. And then we have another trial called PSMAddition that is the castrate-sensitive metastatic disease. And that trial is also accruing. So all these trials are accruing very, very, very well. And I think that's great for patients because if we end up with positive trials, of course we have to wait and see. If we end up with positive trials, patients have more choices, and that's what's really important.

Alicia Morgans: Absolutely. Well, I so appreciate you unraveling this really complex landscape for us, and the complexity is what's going to end up helping patients, I think in the end, having those options and having really good therapies to control their disease, hopefully in multiple states of the disease. Thank you so much for your time and your expertise.

Oliver Sartor: Great. Thanks for having me here.