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Neeraj Agarwal: Hello. We want to welcome Dr. Capucine Baldini, who is the attending physician in the phase I program at the Gustave Roussy hospital in Paris, in France. Welcome, Dr. Baldini.

Capucine Baldini: Hello, thank you very much for having me today. I'm very pleased to talk a little bit about the presentation I have made at ASCO on the phase I results of T-cell engager Pasritamig targeting KLK2.

Neeraj Agarwal: First of all, I'd like to congratulate you and Dr. Stein and the team for the oral presentation at the ASCO 2025 meeting. I personally found the T-cell engager targeting a unique novel target KLK2 on prostate cancer to be quite exciting. And also, congratulations on the JCO publication, which came up almost at the same time. So if you could please tell us more about the drug and why we should feel excited about this molecule.

Capucine Baldini: Pasritamig is a first in class bispecific T cell engager targeting human kallikrein 2, which is a novel target expressed on prostate cancer cells with limited expression in normal tissue. In terms of mechanism of action, pasritamig simultaneously binds to KLK2 on prostate cancer cells and CD3 receptor complexes on T cells leading to T cell activation and subsequent lysis of cancer cells.

This study was a phase I dose escalation and dose expansion study in metastatic CRPC. All patients must have received prior ARPI and/or chemotherapy, and prior radioligand therapy was allowed. In the dose expansion phase of the study, the population of participants was restricted to patients without visceral disease and a PSA over two nanograms per milliliter.

The study started with a dose escalation phase and Sub-Q dosing, and IV was later introduced to reach higher doses. In this study, the MTD was not reached and the RP2D was defined as 3.5 milligrams on day one, 18 milligrams on day eight, and 300 milligrams every six weeks IV. In terms of the analysis of the population, we analyzed two populations. First, the safety or RP2D population, which included patients treated at 300 milligrams every six weeks, either in the dose expansion or dose escalation phase of the study.

And then we analyzed the second population, the safety RP2D population, including patients treated at 300 milligrams either every three weeks or every six weeks. All the doses were outpatient. In terms of baseline characteristics in the overall population of patients treated, participants were heavily pretreated with a median of four prior lines of treatment ranging from 1 to 13.

In the RP2D safety population, all patients received prior ARPI and 76% of patients received prior chemotherapy. Due to the eligibility criteria in the dose expansion phase of the study, fewer patients had actually visceral disease and especially those with visceral disease and especially liver metastases.

The safety profile of pasritamig was favorable across all doses and schedule. On the left hand side of the tornado plot, you can see the most common treatment related adverse events in the overall population of patients mini sub-q and IV dosing. As expected, more patients had injection site reaction in the sub-q dosing, mostly grade one or two. At RP2D, 40% of patients did not have any adverse events, and the most frequent treatment related adverse events were fatigue and infusion related reactions, mostly grade one or two.

And notably, infusion related reactions, did not require the use of steroids nor epinephrine. What was striking in this study was the rate of CRS that was lower than 10% and grade one with fever only, and no patients required, actually, the use of tocilizumab. In terms of high grade treatment related adverse events, the only grade 3 were transient AST and ALT increase, as well as neutropenia that occurred in the patient with a COVID-19 infection.

Altogether, we did not observe any DLT in this phase I study. We also looked at a preliminary efficacy in patients with metastatic CRPC, and we show that Pas achieved rapid and deep PSA responses, with more than 40% of participants actually achieving PSA50, and 36% of them achieving confirmed PSA50.

We then analyzed in the all treated population of patients with measurable disease at baseline, the overall response rate that was determined at 8.3% with a median duration of response of 8.9 months. The other particularity of Pas, were the durable response and durable disease control, with a median RPFS of 7.9 months and patients ongoing actually for more than a year.

We have a patient that is currently still on study for almost three years. PSA50 responses and disease control were also observed irrespective of prior treatment with taxane or PSMA radioligand therapy. So altogether, Pas showed a remarkable safety profile in this phase I study, with low rates of treatment related adverse events and grade 1 CRS with no tocilizumab use.

The safety of the RP2D regimen allowed an outpatient dosing and every six weeks schedule. Finally, in terms of preliminary efficacy, Pas achieved a durable disease control and an RPFS that compares favorably to historical data in heavily pretreated participants with CRPC, and multiple pivotal studies of Pas are currently being developed.

Neeraj Agarwal: These are really exciting data. One of the most striking things I found was really it was an outpatient dosing. Almost every single patient was dosed on an outpatient basis. And this is one of the T cell engagers, which was not associated with any significant CRS syndrome, which I thought was quite striking. And even though this is a phase I trial, the RP2 dose or recommended phase II dosing.

At that dose, the efficacy in these patients with mCRPC who had received four prior lines of therapies, was also quite remarkable 7.6 months, or 7.9 months of RPFS, 42% of these patients achieving a PSA50 responses and duration of responses were quite long. So I think this all is quite remarkable in my view. What do you think?

Capucine Baldini: Yes, so that was very striking to me as a clinician and especially a phase I developer, having some experience with other T cell engagers in prostate cancer, but also in other solid tumors, because mostly, we were more used to seeing high rates of CRS mostly over 50% and most of the time requiring as well the use of tocilizumab.

So it was really surprising to see that with those patients we did not have the use, we did not require the use of tocilizumab, and all the CRS were mostly fever which was really a very manageable with acetaminophen in the outpatient setting. One of the potential explanation also of this cleaner profile is the expression of the targets.

Because KLK2 is very specific to prostate cancer cells and might explain as well this remarkable safety profile. So at first when we were doing the dose escalation study with the sub-q dosing, it became difficult at some point because of the number of injections that were related to the sub-q dosing, and we wanted to increase, of course, the efficacy and also we consider the PK data and we decided to go for the IV dosing.

And all the team was actually very worried about transitioning from sub-q to IV, because obviously the use of sub-q at the beginning was there to mitigate the risk of CRS. But when we transitioned to IV dosing, we did not see an increase in CRS. And on the other end, we found less adverse treatment related adverse events with the IV dosing, which was obviously very reassuring.

It does not mean that we cannot see CRS with this compound, because during the dose escalation, we also push the dose higher. And we saw an increase in terms of the rate of seizures. So the idea was to take into account obviously the efficacy, but also the safety profile to find the perfect recommended phase II dose, which is difficult to target because once again, it's an immunotherapy by definition. So the maximum tolerated dose was not established in this phase I study.

Neeraj Agarwal: So again, I agree with you. Very remarkable data, very promising preliminary efficacy we hardly see in phase I trials, and then remarkable tolerability. Where you go from here?

Capucine Baldini: Yes, that's a great question. I think the setting obviously of development of this drug and where it should be is an important question. I guess I don't have a clear answer, but there are multiple studies that are ongoing with this drug because considering the favorable safety profile, it seems to be a perfect drug to combine with other compounds. So probably chemotherapy, but in my opinion, it would be even more interesting in earlier setting because the disease can still be more infiltrated by immune cells, and we can hope for increasing the response in earlier settings.

So it would be very interesting to see the efficacy of the multiple combinations that will be investigated in phase III studies.

Neeraj Agarwal: That sounds very exciting to me, and I'm sure it will be very exciting to our patients as well. So we look forward to those pivotal trials which are coming up. And congratulations to you to your team, Dr. Stein, for this remarkable work.

Capucine Baldini: Thank you very much. And we are very excited to see the further development of this drug.