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Ashish Kamat: A warm welcome to all of you from the UroToday studios. I'm Ashish Kamat, professor of Urologic Oncology at MD Anderson Cancer Center in Houston, Texas. We're live here in San Francisco at ASCO GU 25. And it's a pleasure to welcome one of my colleagues from M.D. Anderson, Dr. Funda Meric-Bernstam. Welcome, Funda.

Funda Meric-Bernstam: Thank you for having me.

Ashish Kamat: So you have been invited to a GU meeting. It's for all the work that you're doing, some exciting work really with the ADCs and that whole platform. You're going to be talking about TROPION tomorrow and your-- share with us some of the background and the actual abstract and what it means for the field.

Funda Meric-Bernstam: Yeah. Thanks so much. First, it's really a pleasure being here. And as you know, this is-- I'm here in part because of my passion for antibody drug conjugates in general. Over the last several years, we've really seen a significant amount of drug development in this space, and really multiple agents showing significant activity and many recent drug approvals and promise for many others.

A very important target that's emerging is Trop-2. And Trop-2, of course, is expressed across a variety of tumor types and of course recognized already as a target in the context of bladder cancer, urothelial cancer. The presentation is going to be on a phase I expansion, TROPION-PanTumor01. This was the phase I clinical trial looking at datopotamab deruxtecan, or Dato-DXd. That is a Trop-2 targeted antibody with a deruxtecan payload.

This went into a phase I clinical trial initially with a dose escalation in lung cancer. That data was published in JCO presenting the lung cancer data. And as you know, then the drug went on to further develop into lung cancer. Subsequently, we did expansions in breast cancer. That data also was presented in JCO. And very recently, we've had FDA approval for this agent in the context of hormone receptor-positive breast cancer.

This phase I study had multiple different disease-specific cohorts. And the data from the urothelial cohort with the initial data was presented last year by one of my colleagues, the first 18 patients in the cohort. So tomorrow I'll be presenting the data on the 40 patients completely accrued with a 10-month follow up.

This was a heavily pretreated patient population, with about 60% of the patients having had three lines or more of therapy. All the patients had had immunotherapy. The majority of the patients had seen a prior platinum, as well as EV.

So this trial demonstrated that in this patient population, we had significant activity. The objective response rate with central review was 25%. The majority of the patients had disease control, and these were durable responses. In our 10-month median follow up, we had not achieved the median duration of response yet. But the six-month control of the responders was 76%.

So really exciting to see such durable disease control with no new safety signals. This is a relatively safe regimen, with the most common side effects being stomatitis, some nausea. No treatment-related deaths, no meaningful cytopenia, and no neuropathy associated with this agent.

So I think a really exciting signal. And this agent is being further developed in TROPION-PanTumor03. And of course, this data that we're presenting will, I think, support the rationale for that.

Ashish Kamat: Right. I mean, first off, congratulations, because those numbers are really impressive. And I'm glad you brought up the fact that they were heavily pretreated, which, of course, they would be for a phase. But the EV-treated patients. So with the caveats of a 40-patient report, did you notice any signals as to would this ADC have any benefit as a sequential ADC after EV or no signals there?

Funda Meric-Bernstam: Yeah. Thanks so much. In the presentation, we will be demonstrating the data. And when you look at the waterfall plot in this study, there were responses both in patients who have had prior EV and those patients that hadn't. One note that's worthy is that this clinical trial was conducted at a time prior to the data of EV pembro emerging.

So all patients had immunotherapy, and most of the patients had EV, and the patients had not had the combination of these two agents at the same time. But I think it does suggest that after EV, this would be an active regimen. Of course, a lot more, I think, work needs to be done now to figure out how to best position—are there patients that would benefit—what will be the best sequence of therapies. Are there patients that would preferentially benefit from this regimen? But of course, there's always interest in things like ADC combinations. But in this context, I think this is definitely looking like an active regimen that may benefit patients that is relatively safe.

Ashish Kamat: And just to follow up on that, what about combining this with IOs? Any thought process or is that heading in that direction as well?

Funda Meric-Bernstam: Yeah, that's a really great question. Of course, this is a little bit more complex in urothelial cancer, since many of the patients are getting IO with the first line at this point in time. So it will be interesting to see if we had done Dato plus IO after an IO-exposed population, whether that would have fared better than Dato alone. So that information is not available at this time.

That is something actively being pursued in other disease types. So this agent, of course, is in development in lung cancer and is being explored in combination with IO. There are ongoing clinical trials in breast cancer where triple-negative breast cancer is being tested with the Dato immunotherapy combinations.

And also, recently, there was a presentation from the I-SPY clinical trial in breast cancer where in the adjuvant setting, in the immune-sensitive patient population, there seemed signal with the Dato plus immunotherapy combination. So we're all very excited about the idea of, is there genuinely enhancement of immunogenic cell death? And whether across the board there's advantages of that combination, and whether there will be activity in a patient who's already seen immunotherapy.

Ashish Kamat: Right. And of course, we all like to personalize therapy for our patients. So have you done any work or could you share any thoughts that you have on the assays? Like are you looking for Trop-2, either by genomic or IHC, or are you trying to enrich the population in further studies?

Funda Meric-Bernstam: Oh, thank you so much for that question. This is an area of much passion for me, because as you know, in our institutional efforts and more broadly, we're always thinking about, how can we pick the best treatment for each individual patient? In this particular clinical trial, patients were not selected based on Trop-2 expression. Trop-2 is expressed quite frequently across the board in bladder cancer, but I do think it's worth exploring that further.

Initial clinical trials with datopotamab in the context of lung cancer didn't show a clear signal when they just looked at immunohistochemistry and compared expression versus activity. But really beautiful work recently was presented at a lung cancer meeting where they showed with a quantitative imaging strategy that they were able to demonstrate there was a dramatic difference really emerging in the high expressors versus low expressors, looking at both percentage similarity as well as the localization of the membrane versus cytoplasm.

So I do think some more sophisticated imaging tools to help us with the quantitation is definitely coming. But in our own research efforts, we're looking at how do we align relative expression, and whether we can modulate expression. So not related to this clinical presentation per se, but we recently presented published data from our lab, for example, looking at whether we can—where we demonstrated that just getting, for example, breast cancer models, if we identify models that don't express Trop-2, they're not sensitive to Dato. And if we introduce a Trop-2 gene into it, and now it's expressing, they suddenly are active. So clearly, expression matters, but we don't know in the context of this clinical trial. And more work is needed to see whether we can further refine that for clinical use and whether it will benefit bladder patients with urothelial cancer.

Ashish Kamat: So to have the benefit of you here—and I know you do a lot of work along these lines—maybe I could ask you, the localization imaging, clearly you're doing it on tissue. But is there evidence or can you share with us what you know about actually using radiographic imaging for targets such as Trop-2? Any role there in selecting patients? It could be in any disease, right? Not just urothelial.

Funda Meric-Bernstam: Yeah, I know. That's a really interesting question. I think there's a lot of interest in using radiomics to try to identify the molecular features of the tumors. So I'm not aware of any data at this time in urothelial cancer or other diseases, but I do think it's worth starting to look at that because as you know, even histological appearance of tumors has helped guide which patients may have expression of certain proteins. So I do think eventually, we'll be able to come up with integrated ways to better identify patients.

Ashish Kamat: Great. Always a pleasure chatting with you. Thank you so much for taking the time. Enjoy the rest of your meeting.

Funda Meric-Bernstam: Thank you so much for having me.