Brigida Maiorano: Thank you, Ashish. Thank you very much. Yes, this is quite a new kind of analysis, because we basically indirectly compared the EV-303 trial data with the PURE-01 data. We all know that there are many unmet needs in the field of muscle-invasive bladder cancer. For patients ineligible for cisplatin, there is no possibility to use a neoadjuvant therapy, or at least there was no such a possibility before the EV-303 trial data were published. But our group already conducted a single-arm phase two trial, which was very important, the PURE-01 trial. Which introduced the possibility to use a neoadjuvant immunotherapy, in that case represented by pembrolizumab for the same setting of patients. So patients with muscle-invasive bladder cancer, but ineligible for cisplatin. This analysis compared two very, very different trials. We know because they are large randomized phase three trial compared to a single-arm phase two trial. But there was this indirect comparison between the two trials regarding the EFS data. We showed that with graphical reconstruction, so there is an indirect comparison of patients IPD-level data. In this indirect comparison, there was no significant difference in the event-free survival between the two data. Of course, they are very different kind of patients because for example, there were more T3, to T4, and node-positive patients in the EV-303 trial compared to the PURE-01.
Ashish Kamat: Let me stop you a little bit for our audience to understand, because again, when someone hears IPD, they think you went out and got the IPD data. Share with us a little bit as to how you do this reconstruction.
Brigida Maiorano: Yes, this is a statistical method originally described by Guyot. So this is built with a digital tool which can digitalize the original Kaplan-Meier curves. We can extract the single data from the curves. And we rebuilt the number at risk at different time points, and we did also some landmark analysis at six, 12 and 24 months. So this is basically a graphical reconstruction of the Kaplan-Meier curves, which allows for indirect comparison and visual representation of the curves.
Ashish Kamat: And it's a validated-
Brigida Maiorano: Oh yes.
Ashish Kamat: Paradigm and procedure. No, I just wanted to make sure, because otherwise some people think that it's an actual IPD analysis, right.
Brigida Maiorano: No, no, no, it's validated.
Ashish Kamat: Exactly, exactly.
Brigida Maiorano: Very, very interesting and validated.
Ashish Kamat: Great. Yeah. And your bottom line findings?
Brigida Maiorano: The findings were that there was no statistically significant, of course, in this indirect comparison between the EV-303 findings and the PURE-01 findings regarding the event-free survival. The two studies had different pathological complete response. Of course, that of the EV-303 trial was very high, around two out of three patients had a pathological complete response. In the PURE-01, it was around 39% at the most recent five-year follow-up. But in our analysis, the event-free survival was quite comparable. And I think this is like a provocative work to try to understand which real contribution the EV adds to the pembrolizumab arm. We know that the EV-303 trial, at the beginning, had also the pembrolizumab monotherapy arm, but they prioritized the EV pembrolizumab comparison. This is a provocative work to explore better which contribution we can add to the perioperative immunotherapy and to design trials that can separate the neoadjuvant and the adjuvant contribution in the perioperative setting of muscle-invasive bladder cancer, to maximize the efficacy while minimizing potentially unnecessary toxicity for our patients.
Ashish Kamat: Yeah. No, very important. And of course, the initial study, as you said, had the pembrolizumab, and then I think in 2022 or thereabout that-
Brigida Maiorano: Yes.
Ashish Kamat: Decided to stop that. And now we're left with these great results, which is great. Don't get me wrong.
Brigida Maiorano: Great. Very good.
Ashish Kamat: We believe are great results, but now we don't know, should we continue? What was the contribution of components? And I think an analysis such as yours, like you said, is very provocative because obviously you can't, I mean, you shouldn't be doing cross-trial comparisons unless you do it in a control way like you did. But if I had to push you and say, okay, let's be provocative, what's your thought, not just based on your analysis, but overall looking at it, where do you think the adjuvant arm comes in? Do you think we should be using data such as yours, the ctDNA data from IMvigor to inform maybe this paradigm, even though it wasn't built like that. What's your sense?
Brigida Maiorano: I think from a methodological point of view, we should generate comparative data, so real and direct comparative data between arms in which the two treatments are administered together and arms with a de-escalation strategy. Maybe we should use some biomarkers that already come from the NIAGARA and also the adjuvant trials. I'm particularly attracted by the ctDNA data, so I think that ctDNA could be used in the future to design some of the intensification strategies. But overall, I think that if we wanted to generate the strongest evidence, direct comparisons are necessary in this setting.
Ashish Kamat: Yeah, no, absolutely. And there's no substitute for an actual direct-
Brigida Maiorano: Yes.
Ashish Kamat: Comparative trial, but clearly once we get standard of care that's evolved, it's going to be harder to enroll patients on the studies, but we need to do that. Thank you so much for taking the time. Always a pleasure.
Brigida Maiorano: Thank you very much.