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Zach Klaassen: Hi, my name is Zach Klaassen, I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We're in Chicago for ASCO 2024. I'm delighted to be joined today by Dr. Scott Tagawa, GU Medical Oncologist, Weill Cornell Medical Center. Scott, thanks so much for joining us.

Scott Tagawa: Thanks very much. Happy to be here.

Zach Klaassen: So we're going to talk today about the final results of your phase I/II trial, looking at dose-escalation of lutetium PSMA. And so obviously, radioligand therapy is everywhere these days. What was the background rationale for designing this phase I/II looking at escalating therapy?

Scott Tagawa: So it was a study designed back in 2016 and started January 2017. So really before we had any randomized data, we started to have the beginning of some of the Australian data, and obviously the retrospective German and other country data before that, and we had been working with the antibodies for a long time.

Zach Klaassen: Sure.

Scott Tagawa: But we wanted to do dose-escalation, as in like we do with medical oncology, a little bit different than what nuclear medicine has done, but traditional dose-escalation. When I say dose-escalation properly, it would be increasing radioactivity amounts per injection, looking at DLTs, basically. The same way we do, typically, for drug dose-escalation. That being said, we chose to go with our prior data with the antibody J591, where it looked like the best regimen was a fractionated regimen, another way to say that would be a dose-dense or dose-intense regimen. So if we're really going for cure of patients with advanced disease or maybe an early disease, to have a constant high dose, and this I actually do mean dose to the tumor without a break. So the half-life of lutetium is about a week. So two weeks in, you still have a reasonable amount and you hit it again. So it's a pretty reasonable dose to the tumor for a constant month rather than waiting six to eight weeks after. And that's the way to kind of breed resistance. So it was using that regimen with a dose-escalation starting off with 7.4 gigabecquerels split.

And then going up to 22.2 in different cohorts. And for phase I, we didn't hit the endpoint. We didn't hit a DLT. So we called the recommended phase II dose, that 22.2 gigabecquerels and then expanded to phase II. So there are 24 patients. The phase I component had 26 more, so about 50 at the recommended phase II dose. And the main efficacy readout was PSA. We looked at other things too. This was started at a time when we did have an IND for a Gallium-68 PET, but it wasn't fully available. So everyone had some sort of PSMA imaging because we at least looked at the gamma expression SPECT from the lutetium.

But not everyone had a pretreatment PSMA PET. Part of it was, there was a shortage of gallium generators during the study. And our second site, Tulane, didn't have an IND, was not able to do PET on their own. So not everyone had that. But when we did look at baseline PSMA imaging by PET and those who had it, they all had some uptake, although four-ish of the patients kind of didn't meet the VISION criteria. The reason I say four-ish is that three out of those four had low uptake lymph nodes. Lymph nodes all didn't necessarily meet that 2.5-centimeter cutoff for VISION. One clearly was negative in a visceral metastasis, but positive in other areas.

So anyway, it was treated, but despite no PSMA selection, interestingly, we did see a PSA response rate that is similar to VISION, which was 54% PSA50 unselected patient population, perhaps because of the dose intensity. And then again, it's a non-randomized time to endpoints whether or not that's valid, but an 8.3-month rPFS and a 17 and a half month or so, overall survival. So with the single cycle of the dose-intense regimen, efficacy looked interestingly similar in a pre-treated patient population to what we see in a selected patient population.

Zach Klaassen: So going back to the patients, were these heavily pre-treated? What did these patients look like from that previous treatment standpoint?

Scott Tagawa: The minimum entry criteria were at least one ARPI taxane exposed or ineligible or refused taxane. So obviously, everyone had at least one ARPI. The majority had two or at least two. The majority, not by a lot, but 60 or so percent, off the top of my head, had prior taxane. Like other trials, about 20% had radium exposure. Two actually had prior lutetium PSMA exposure.

Zach Klaassen: Oh, really? Okay.

Scott Tagawa: J591 from older trials. The entry criteria were kind of agnostic for that. So fairly heavily pre-treated, maybe a little less so than envisioned because we didn't mandate the taxanes, but pretty heavily pre-treated, and I already said this, but unselected for PSMA.

Zach Klaassen: And it's some really interesting data about ctDNA. It's been a big meeting in prostate for ctDNA. I know yesterday at the oral session there was a great figure of how much ctDNA information is being processed here. Just tell us a little about your data from a ctDNA standpoint.

Scott Tagawa: So a secondary exploratory endpoint is looking at different biomarkers and that includes genomics, thanks to PCF and DoD for funding this. We got archival tissue and that on most patients was available. Everyone had plasma. So we looked at plasma circulating tumor cell DNA with the PCF select platform. And the two things that stood out in this relatively small data set were AR copy number gains, whether that's related to PSMA, whether it's related to DNA repair, I don't know. But across the board, it kind of looks to be a poor prognostic sign. And that's all I can say in an unrandomized trial. But copy gains were associated with fewer PSA50 responses and shorter overall survival.

Allele-specific ploidy, we worked with Francesca Demichelis and her team and they've published on this. Diploid did better than having altered allele-specific ploidy, both for PSA responses and overall survival in univariate analysis. Some of this washed out a little bit. In multivariate analysis, it was more just a trend, but I think that it just may be it was only a 50-patient trial. So it's very much in line with other data sets. So I think the first two data sets were this plus Australia, not so surprisingly. And they've also seen AR copy number and at this meeting, not all have related to that, but many have also related to that. Again, short of the randomized data, unclear if that is a prognostic factor or a predictive factor, but it's at least prognostic.

Zach Klaassen: And we saw some cool stuff from Johann de Bono too, in terms of ctDNA clearance, and really looking at that in the PSMAfore trial. So it seems like that's going to be part of our follow-up regimen for some of these patients as well.

Scott Tagawa: Yeah, we'll see. We have twelve-week plasma. We just sequenced it, actually, we haven't analyzed it yet. So we'll look at that. We haven't looked at the quantification, so that was quantification. But we'll also look for quantification and changes. Not expecting to see many changes in those that respond other than lower amounts, but we will see what happens also at progression.

Zach Klaassen: Awesome. Just in terms of tolerability, how did you see these patients tolerate this versus maybe a classic VISION treatment regimen?

Scott Tagawa: So like I said, no DLTs, that was a twelve-week DLT assessment period. That does not mean no toxicity. So xerostomia was the most common adverse event, mostly grade one. I'd say that, that is an adverse event that is a little bit dependent on who's asking the questions. We tend to ask the questions fairly vigorously. And have a higher number than some other people.

Zach Klaassen: Sure.

Scott Tagawa: I'll come back to the adverse events.

Zach Klaassen: Okay.

Scott Tagawa: Overall, this did employ patient-reported outcomes, FACT-P, as well as the VPI short form, a plug for FACT-RNT. I think that is now somewhat validated and has been embedded. And I think that may be better than some of these other factors because CTCAE has some things to be desired with certain adverse events, and that includes dry mouth. But anyway, dry mouth was the most common, fatigue, nausea. So even VISION suggested pre-medication. We didn't pre-medicate for any of those. Again, generally grade one and short-lived. Hematologic toxicity was there, but despite going up to 22.2 gigabecquerels, really the only patient that had grade four hematologic toxicity was progressing and we biopsied, his bone marrow was full of tumor.

But these are what I'm talking about. Treatment-emergent, not necessarily treatment-related. So anyway, overall "well tolerated." I'd say that in line with available data about quality of life, but at least not a lot of high-grade adverse events with CTCAE. This is our mature data. So we do have longer follow-up and haven't seen any significant additional AEs, but it still is relatively short follow-up if we're talking about movement is significantly forward, like PSMAddition or even earlier where I think certain organs could be at risk, such as the kidney of the bone marrow, et cetera.

Zach Klaassen: So where do you see this sort of dose regimen going in the next, say, couple of years?

Scott Tagawa: So to take a step a little bit more broadly, I like the idea of this fractionated dosing. It's partly self-centered because we've done these three different drugs and come up with this fractionated dose regimen. This particular drug in the STAMPEDE2 trial is being looked at in, not the exact but an offshoot of this kind of fractionated regimen one week apart with dosing. So we'll see what happens there, not randomized against the different cycles. So the drug that used to be called LutetiumJ591 is now called TLX591. Their phase III ProstACT trial is using this fractionated dose regimen. And with Actinium-J591, which is now called CONV01-α, Convergent's, they're moving forward with a fractionated regimen with the Actinium-225 radiolabeled antibody. So both with antibodies as well as small molecules, I think it looks interesting. Certainly some science behind it in terms of the dose intensity, et cetera. Zero data randomizing versus the different cycles-

Zach Klaassen: Conventional-

Scott Tagawa: That are out there.

Zach Klaassen: Great conversation as always. Maybe a couple of take-home points for our listeners about your trial.

Scott Tagawa: So importantly, there have been zero true dose-escalation studies for the approved drug. And I'm proud of being able to share some of this data not for me, from our team, that it looked to be safe. And I think that there might be better optimization of what we have, both in terms of amount of injected activity and probably schedule. So I think there's room to work. So luckily, we have works, but I think we can improve upon that. There's early safety data. I think all of these trials combined need longer-term follow-up. And then biomarkers, and I have time to talk so much about the PSMA imaging, but that is fairly, clearly there. SUVmean, et cetera. Some of these tools that are emerging to be able to come out, especially with AI tools. And then, the amount of circulating DNA, particularly the tumor fraction, as well as certain alterations. Looked at least to be prognostic and some could turn out to be predictive in the future.

Zach Klaassen: Outstanding. Thanks so much for joining us in your expertise, Scott.

Scott Tagawa: No problem. Thanks for the invite.