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Elizabeth Plimack: Hi, I'm Betsy Plimack. I'm here at ASCO 2025. We're going over some of the bladder data presented this morning. I am a professor of GU medical oncology at Fox Chase Cancer Center in Philadelphia. And I'm really pleased to be joined by my colleague and friend, Andrea Necchi, Professor of Medical Oncology at San Raffaele Hospital in Milan. Andrea, welcome.

Andrea Necchi: Thank you, Betsy. Thank you.

Elizabeth Plimack: So you gave a great presentation yesterday on your investigator-initiated SURE-02 trial. First, congratulations on getting that trial up and running and almost completed. I noticed this was an early peek at early data. Some of your patients are still getting treated on your study, so we'll see more data later. But tell us a little bit about the study design, the rationale for this study, and then what we learned so far.

Andrea Necchi: Yeah. Thank you. It was a tremendously difficult journey, you know, because SURE-02 study was built based on the premises built by PURE-01 with pembrolizumab monotherapy, SURE-01 with sacituzumab monotherapy neoadjuvant. This study was conceived as a classical neoadjuvant studies with systemic therapy upfront, surgery, radical cystectomy, and observation.

SURE-02 study actually started the same way, started as a classical perioperative study with the combination therapy of SG pembro neoadjuvant for four cycles, radical cystectomy, and a maintenance pembrolizumab phase. But we soon realized that-- and we soon had a lot of protocol deviations, almost 100% of the patients achieving a deep response in the neoadjuvant therapy, declined cystectomy.

So it was a very, very challenging and deep endeavor for us. And we had to reshape our mind, and we had to reshape the design of the study that was otherwise dead in order to allow the possibility to keep the bladder intact in the patient. So we amended the study. We took a lot of time and a lot of effort to doing this and pushing this as soon as possible in order to allow a neoadjuvant part, multidisciplinary discussion, allowing a re-TURBT depending on patient preference and depending on the response to treatment assessed with imaging, and then the maintenance pembro.

So actually, SURE-02, this way, according to the patient, what the patient actually told us to do in this journey became a bladder sparing-- let's say, response adapted and patient-driven bladder sparing approach.

Elizabeth Plimack: I love that. I think that's the perfect way to explain it. So I'll say, we share enthusiasm for bladder-sparing approaches using systemic therapy to clear the bladder of cancer and keep it in place. I'm so delighted that our teams and many others now are working on this. It's definitely what patients want. So kudos to you for continuing to move that forward, and we're right along with you doing the same.

Andrea Necchi: Yeah, you inspired us in this journey.

Elizabeth Plimack: Together.

Andrea Necchi: We did the RETAIN study.

Elizabeth Plimack: It's great.

Andrea Necchi: RETAIN-1, RETAIN-2 study. They are just on the same line.

Elizabeth Plimack: The more the better. So we're just thrilled to see this presented and to see it as an oral presentation. Let me ask you a little bit about the neoadjuvant component. You chose two different drugs than our standard. Tell me a little bit about why you chose those two. And then what conversations did you have with patients at that point where they're deciding whether to go on your study or whether to get neoadjuvant, for instance, or still send some back?

Andrea Necchi: Yeah. Well, as I mentioned in the discussion part, the study was actually shaped according to the patient preference. It's clear. It was clear since the PURE-01 period. The patient population that came to our center is a very, very select patient population who were searching for something different from standard chemotherapy or were ineligible to receive standard chemotherapy and raise the bar very high and higher and higher during the treatment course, depending on the response. At that point, they also questioned the need to undergo standard bladder-sparing approaches like radical radiotherapy.

So whenever they achieve a deep response to treatment, it was pembro monotherapy or saci monotherapy or the combination of the two. They said, OK, Doctor, why I have to go to the operating room, and why I have to receive an impactful treatment, a radiotherapy in the bladder, in the pelvis? Particularly in the younger, young females and young men and so-- with regard to the use of the drugs, SURE-02 study was conceived simultaneously to SURE-01. At the time, the topics for that were still ongoing, were still not released. So there was enthusiasm towards this drug. 

And I still think that the drug could be there. Pembro data are easily addressable to us because we can spend our experience with PURE-01. It's a great experience, and we have data presented at this meeting with long-term, five-year follow-up of these patients. They did pretty well.

So we were all enthusiastic of using pembro. So the combination of the two, in our mind, what could have been able to still overcome the limitation of the immunotherapy call to a more so immunotherapy-resistant tumor. And the patients were on our side with this regard. In general, patients that come to our center are patients that are searching for clinical trials.

Elizabeth Plimack: Right. And this is what you offer.

Andrea Necchi: So it's not something that cannot be generalized on the community practice or the community level or smaller hospital. It's a very, very select patient population that come to us already with the idea of searching for something different. So our job is relatively easy because we are already embarking in the same direction the patients are asking us at the time that we meet for the first time the patient, because the patient come to us for this particular goal.

Elizabeth Plimack: So you're using this novel combination. There was certainly enthusiasm at the time of trial design, and you're showing some results with efficacy. We're definitely seeing that. Where are you going next? So are you taking this combination forward, either in a bladder-sparing approach, taking another tack toward bladder sparing? I assume it will embed immunotherapy because we're all looking to that.

Andrea Necchi: Yes.

Elizabeth Plimack: What's next?

Andrea Necchi: Yes. So let's start from the interim endpoint, the clinical responses that we are seeing. The data are still flexible, depending on the dynamics, but something around 35% to 40%. This is promising.

Elizabeth Plimack: You're talking about clinical complete response rate.

Andrea Necchi: Clinical. So imaging negative result and negative biopsy, negative re-TURBT. But most importantly, I'm much more interested in the biomarker development. And in principle, studies like the SURE-01, SURE-02 are conceived to bring hints for next developments rather than setting the stage for new therapies that could be expanded in further trials.

Our precise aim is to provide hints. And with regards to biomarker, there is a story that is emerging that's quite intriguing story that is pointing to the role of luminal subtype as a potential way of selecting better patients who are more likely to respond to TROP2 targeting. That could be sacituzumab, or other TROP2 ADCs in the near future.

And interesting to see that the profile of responding patients in SURE-02 is-- according to the molecular subtype-- is completely different from pembro monotherapy. There is an enrichment in luminal subtype responders, and luminal subtype is enriched in TROP2 gene expression, HER2 expression, and we saw a lot of HER2 mutation, also, the DNA level, in clinical complete responders.

Elizabeth Plimack: You're comparing your pembro-only trial--

Andrea Necchi: Exactly.

Elizabeth Plimack: --to SG pembro.

Andrea Necchi: With the combination--

Elizabeth Plimack: And you really have that power, then, to look at differential biomarkers. Yeah.

Andrea Necchi: And the same data pointing to luminal subtype are also confirmed by the biomarker data that are emerging in SURE-01 with saci monotherapy. So meaning that there could be a possibility in the near future, with newer trials, maybe using different anti-TROP2 ADC. We don't know.

Selecting patient based on luminal subtype to have an enrichment in complete responders and be able to overcome cutoff of, let's say, 50% and become much more attractive in a strategy of bladder-sparing approach that is dependent on response. We need a bit more than 40%, 44%.

Elizabeth Plimack: We do.

Andrea Necchi: I don't think that this is a range for potential success, as the new form of therapy.

Elizabeth Plimack: Well, that's where we're stuck, right? It's sort of where we've landed with all of these--

Andrea Necchi: We should overcome the 50% response rate in order to see, OK, this combination therapy is the next-generation combination therapy. And in order to do this, maybe we could focus on the biomarker selection.

Elizabeth Plimack: I love that. Andrea, thank you so much for this really impactful work, not only getting this study off the ground, designing it rationally, incorporating what patients want, which is bladder sparing, and all that strong biomarker work that we just scratched the surface of today. So I encourage everyone to stream your presentation. It was excellent. And thank you so much for this discussion.

Andrea Necchi: Thank you so much for the discussion. Thank you, and thank you today. Thanks.