Daniel Petrylak: Hello, my name is Dr. Daniel Petrylak. I'm a professor of medicine and urology at the Cancer Center at Yale University. And we're talking about the NeoSTOP-IT Phase II study for bladder preservation with Dr. Alexander Wei. Dr. Wei, why don't you give us a description of your study?

Alexander Wei: Yeah, I'd be happy to. So I'm Alex Wei. I'm one of the genitourinary medical oncologists at Columbia. And here at Columbia, as I'm sure you may still remember, Dan, we do have a focus on bladder preservation and bladder sparing therapies for patients with muscle invasive bladder cancer.

This is something that we've done for a while. And it's something that we wanted to continue the research on. So the study NeoSTOP-IT is our phase II clinical trial where essentially we're giving patients a chance to preserve their bladders after neoadjuvant PD-1 and GemCis with or without an anti-LAG-3 agent as well. And essentially, if patients achieve a clinical complete response after four cycles, they can choose to go on maintenance immunotherapy instead. And that's either with single-agent PD-1 cemiplimab in this case, or dual-agent cemiplimab and an anti-LAG-3 agent to complete one year of therapy.

So this is something that we're excited about. And we think that it should accrue quickly given the significant interest by patients for bladder preservation therapies.

Daniel Petrylak: What's been your preliminary experience with this thus far? How many patients have you entered thus far?

Alexander Wei: So we're expecting IRB approval today. So far we haven't enrolled anyone. But we've done a very similar strategy off-label for a while. And patients have done quite well.

Daniel Petrylak: So I guess you would power this for a complete response rate of 30% or higher. Is that what you would expect?

Alexander Wei: Yeah. So the way that we did it statistically was we're aiming for a clinical complete response rate of 70% which is obviously a lofty goal.

But we also had to make the trial feasible. And that's in comparison to the clinical complete response rate of 43% from Matt Galsky's GemCis plus nivolumab study.

Daniel Petrylak: Terrific. How many patients do you expect to enter?

Alexander Wei: So we're expecting to enroll a total of 36 patients. 24 into the GemCis cemiplimab and fianlimab arm, and 12 into the GemCis cemiplimab arm. So it is going to be randomized 2 to 1 whether or not you get the LAG-3 agent.

Daniel Petrylak: Terrific. And what biological correlates will you be looking at? I'm sure you've got some correlative studies that are going to be performed.

Alexander Wei: Yeah. So we've been fortunate to work with Michael Shen's lab here at Columbia, who is renowned for being able to generate bladder-derived organoids.

And our intention is to generate organoids from patient derived samples, pre-treatment, post-treatment, and potentially even on-treatment if patients have residual disease. So we're going to compare these organoids and sequence them and see how their tumor environment and microenvironment are different.

We're going to look for signals of treatment sensitivity but also treatment resistance. We know that there is a signature that exists for chemorefractory patients. But we wonder if we can overcome this with the PD-1/LAG-3.

We're also going to have urine and plasma banked. We're going to do circulating tumor DNA in both urine and in plasma. And we're going to use that not to guide treatment, but potentially to also be another marker for a biological correlate.

Daniel Petrylak: Have you seen that circulating tumor DNA influences a patient's decision as to whether they will keep their bladder?

Alexander Wei: I think that it's not going to trigger decision-making on the trial. But we do know that it's going to affect their prognosis. So if a patient has low-positive circulating tumor DNA but their scans are negative, it's not going to change our recommendation that they can choose to defer cystectomy if they want.

Now, we also know that residual muscle-invasive tumors can lead to positive ctDNA. And after surgery these patients end up being negative. They just need time to clear the ctDNA and the tumor. So if a patient elects to keep their bladder with a negative scan but positive ctDNA, I think that's a reasonable decision.

Daniel Petrylak: So Dr. Wei, there's a pending approval of pembrolizumab in muscle invasive urothelial carcinoma. Do you expect that there will be any issue in terms of accrual?

Alexander Wei: I think that's a very good question and something that we've definitely thought about. EV-pembrolizumab (enfortumab vedotin plus pembrolizumab) is an effective regimen. In the advanced setting it's heads and shoulders above everyone else.

But in the neoadjuvant setting and the curative setting, I think there are other factors that we need to consider. One, we don't know if we're going to see the same translatable overall response rate. I think we would like to see it, but that's for sure.

But we also know two things. One, EV-pembrolizumab is not without its long-term side effects. The rash we can get over sometimes, but the neuropathy is arguably far worse and longer lasting than the neuropathy that you might get from platinum.

And the second thing is that GemCis immunotherapy is an effective combination. It's not like we're giving a patient substandard therapy, we know that it works.

So I think the question for me is not so much is the regimen in NeoSTOP-IT going to be better than EV-pembrolizumab. It's more can we add another tool to our armamentarium to treat muscle-invasive bladder cancer and give patients an option to keep their bladders. And who knows, maybe the answer in the future is some combination of everything.

Daniel Petrylak: Well, the interesting thing is we did present our updated data on EV by itself in cisplatin-eligible patients as neoadjuvant therapy. There's about a 25% rate of neuropathy even with three courses. So my experience has been the neuropathy once it develops doesn't go away.

Alexander Wei: We've seen similar things.

Daniel Petrylak: Yeah, exactly. But this is an exciting time for bladder cancer. It's great that we have these options. We look forward to the study being completed as well as the results. So good luck and thank you for the overall description.

Alexander Wei: Happy to talk about it. And if you have patients in the Northeast that want to keep their bladders, we're happy to see them at Columbia.

Daniel Petrylak: Sounds good.