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Sam Chang: Hello, everyone. We are at GU ASCO 2024, and my name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we're quite lucky to have Dr. Matt Galsky here from New York City, who will be talking to us about the ANTICIPATE II trial, which is looking at an agent, APL-1202, with tislelizumab, I think is the correct pronunciation of an immunotherapy agent.

Matthew Galsky: That's right.

Sam Chang: So Matt, thank you for being with us here. And give us a short synopsis of this ANTICIPATE II trial.

Matthew Galsky: Absolutely, yeah. Thanks for having me. So APL-1202 is also known as nitroxoline salt. Nitroxoline is very interesting. It's actually been available in Europe for a long time as an antibiotic. It's orally bioavailable and achieves high concentrations in the urine. So some interesting properties. But it's been known to have anti-cancer properties for a long time.

And in a paper in JNCI in 2010, in a drug screen for MetAP-2 inhibitors, when angiogenesis inhibitors were quite big, nitroxoline was identified. So probably one of the mechanisms of action. In that same paper, they showed that in orthotopic bladder cancer models, nitroxoline had anti-cancer effects. So this molecule has been of interest for a while.

Sam Chang: And it's been around. It's been used.

Matthew Galsky: It's been around for a while. It's been used, safe, orally bioavailable. Interestingly, in recent studies in bladder cancer cellular models, APL-1202 has been shown to induce immunogenic cell death. So all the hallmarks of immunogenic cell death, suggesting that possibly there are mechanisms aside from MetAP-2 inhibition and that this might pair well with PD-1 inhibition.

So that led to some in vivo models in bladder cancer, which indeed showed at least additive effects with anti-PD-1, leading to the design of the ANTICIPATE study.

So the ANTICIPATE study is neoadjuvant therapy, patients with clinically localized muscle-invasive bladder cancer who are cisplatin-ineligible or who decline cisplatin-based neoadjuvant chemotherapy.

And it's a study that involves two phases. There was a phase I dose escalation phase to determine the recommended phase II dose, and that was completed. And then an expansion in a randomized phase II design. And the randomized phase II includes giving APL-1202 plus tisle, so the combination, versus tisle alone. And the randomized phase II has a two-stage design. So right now we're looking at the interim results of the phase II portion.

Sam Chang: And that's looking at either the... And with the dose escalation, was it escalating the APL-1202, or is the tisle dose known, or is a combination raised?

Matthew Galsky: Great point. So tisle's been around in China, a PD-1 inhibitor used in multiple malignancies. So that dose has been known and is fixed.

Sam Chang: And known. Okay.

Matthew Galsky: And so APL-1202 was dose escalated.

Sam Chang: Got it. Got it. So once you got to that dose, and then looking at basically a neoadjuvant administration of either the combination or tisle alone.

Matthew Galsky: That's correct.

Sam Chang: And what did the results show?

Matthew Galsky: So three cycles, neoadjuvant therapy and then surgery. The primary endpoint for this phase II portion is the pathologic complete response rate.

Sam Chang: Okay. At the time of cystectomy.

Matthew Galsky: At the time of cystectomy.

Sam Chang: Got it.

Matthew Galsky: So smallish cohort so far, about 40 patients. With the combination, the path CR rate is 39%. With the single agent, it's 21%. Obviously, these are not meant to be comparative at this small size, but both of those arms met the pre-specified threshold to advance to stage two of the two-stage design. So the study has been expanded, and it's actually completed enrollment but we don't have the final results yet.

Sam Chang: Got it. And so both arms basically expanded since both showed at their pre-designated kind of success points that hey, we can advance. And tell me about side effect differences.

Matthew Galsky: Yeah. So if you look at the treatment-emergent adverse events on the two arms, numerically they're a bit higher with the combination treatment. And what you see in terms of those higher side effects, there's a little bit more anemia and there's a little bit more lymphopenia. So certainly things that are, quote-unquote, manageable from a treatment standpoint. We don't seem to see an exacerbation of immune-related side effects with the combination compared to tisle alone.

Sam Chang: And when looking at the dosing, the tisle is every three weeks?

Matthew Galsky: Tisle is every three weeks.

Sam Chang: And then the oral medication is once daily throughout that time period.

Matthew Galsky: Once daily continuously. Right.

Sam Chang: Okay. And so in terms of those patients with the pathologic CR as opposed to the side effects, did we see any relationship? Those that had more side effects, perhaps more likely to have a CR? Or too early to tell perhaps with such small numbers.

Matthew Galsky: Too early to tell. Hasn't been analyzed in detail, but that'll be something interesting to look at.

Sam Chang: Okay. All right.

Matthew Galsky: I will note too that even though numbers are very small, path CRs were seen in patients with clinical T3 disease on the combination arm, but not on the single agent arm. The only path CRs are with clinical T2 disease, for what that's worth.

Sam Chang: Interesting. Interesting. So perhaps... Well, early on, as you said. Not a comparative kind of evaluation of the data, it's early. But we clearly see a signal with a benefit of the combination of those two.

And so let's say we get these results back, it's a year or so out, I don't know exactly when, and we see similar results. How would this then stack up? What's the next step then after that?

Matthew Galsky: So clearly in the cisplatin-ineligible space in terms of neoadjuvant therapy, the current standard of care is no neoadjuvant therapy, straight to cystectomy.

Sam Chang: Correct.

Matthew Galsky: Trials are ongoing with EV + pembro in that setting. And EV + pembro clearly a very effective treatment in the metastatic setting.

Sam Chang: In the advanced setting. Sure.

Matthew Galsky: A very different side-effect profile than giving an oral drug plus PD-1 inhibition, based on the side effects that we've seen in ANTICIPATE so far. So, in that more frail, if you will, population, I'd say... We have to be careful saying "frail" in a population of patients that can have a cystectomy.

Sam Chang: Have a cystectomy. Right. Right.

Matthew Galsky: But in patients who might be a little bit more borderline in terms of functional status, I think that if the results stack up in terms of safety and activity, there could be a role for another treatment option in those patients.

Sam Chang: So let's go a little bit beyond this particular abstract and look in the neoadjuvant population, and how from the get-go, there's a differentiation between those that can get platinum versus those that can't.

If you were a patient, and knowing the toxicities associated with the different treatments up there currently, and you were platinum-eligible, would you still choose a platinum-based neoadjuvant strategy?

Matthew Galsky: So today, yes, this platinum-based neoadjuvant therapy. Whether or not that's the answer in 12 months, I think, remains to be seen. We have phase III reading out.

Sam Chang: We'll see other trials that read out. Exactly. And so, in this population currently, for a urologist who does cystectomies and refers for neoadjuvant treatment, there's always an ongoing discussion on who really is, quote-unquote, "platinum-eligible." And you've been obviously quite the leader in terms of helping determine the criteria for those who should or who shouldn't get it.

In your mind, we know the absolute benefit of neoadjuvant treatment in terms of numbers. If you had clinically localized T2 cancer, one that perhaps could actually even be a candidate for bladder preservation and bladder sparing, would you still get neoadjuvant chemotherapy, or would you proceed to have a very quick and timely radical cystectomy? Tough question. Hypothetical.

Matthew Galsky: So in a cisplatin-eligible patient?

Sam Chang: Correct.

Matthew Galsky: So in a cisplatin-eligible patient, I think the challenge has been that even though we think we know who the patients are with clinical T2 disease, clearly, we're not very good at determining that. And so the challenge is that you just don't know for sure that the patient has clinical T2 disease. We know in randomized studies there's a survival benefit. And so, unless there's an absolute contraindication, I would use the best treatment that we have.

Sam Chang: And that's, honestly, I think now that's the bias of most surgeons, which I think has changed over time. Clearly, we were chemotherapy, somewhat, not antagonistic, but perhaps resistant. And I think that's really kind of shifted to the point where we understand the benefits of multidisciplinary care and the neoadjuvant treatment.

So the next steps with ANTICIPATE then, you think, is we'll get the readout. Assuming that it's positive, where do you think it will go next, this combination?

Matthew Galsky: So if the randomized phase II is positive, then a phase III study would be designed to help support those results.

Sam Chang: Great. Great. Matt, thank you as always. Appreciate your insight and your wisdom and your experience. And thanks for spending some time with us.

Matthew Galsky: Thank you.