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Alicia Morgans: Hi. I'm so excited to be here today with Professor Maria De Santis, who is joining me to talk through her presentation at ESMO 2024 where she reviewed very exciting bladder cancer abstracts.

Thank you so much for being here today, Professor De Santis.

Maria De Santis: Yes. Hello, Alicia. It is a real pleasure to be here. We had a really exciting ESMO, and I'm happy to review some of the data of the mini-oral session with you.

So the mini-oral session started with the TAR-200 abstract LBA85. It is about non-muscle-invasive bladder cancer in the BCG-unresponsive disease, in particular focusing on the carcinoma in situ. So we have different goals and challenges in the treatment of BCG-unresponsive NMIBC, and this includes that we want to preserve the bladder. The patients want to keep their bladders. We need to avoid recurrence and progression to muscle-invasive disease or metastasis.

For that, we need a high CR rate with our treatments and, in addition, durable CRs of 12 months or more. These are the usual endpoints, and low side effect rates because it is about a longer-term treatment. How can we achieve these goals? We need to optimize the use of available agents, for example, and, with that, improve intravesical delivery, intensify treatment, looking into combinations. Here, we also need to look into risk-benefit rates for these patients, or we can introduce novel drugs.

There are different ways to improve intravesical delivery, and this includes hyperthermia, hyaluronidase, nanoparticles, hydrogels, and mechanical delivery.

Here we are, TAR-200 is a novel gemcitabine intravesical system, and this is designed for persistent therapeutic drug levels over an extended period of time. TAR-200 is charged with 225 milligrams of gemcitabine, which is an active drug within the bladder, and it is put into the bladder and renewed every three weeks.

This is the study design of SunRISe-1. It is an ongoing open-label phase 2B study. It is in patients that have CIS with or without papillary disease. It had three cohorts: TAR-200 plus cetrelimab, TAR-200 monotherapy, or cetrelimab monotherapy.

The first two cohorts—no, it was Cohort 1 and Cohort 3 actually—were closed, and Cohort 2, the TAR-200 monotherapy, was expanded to 85 patients, and these were presented at this ESMO meeting.

The primary endpoint was the CR rate, and these are the results. What you can see here is a very high CR rate of 83.5%.

What else can we see on the right-hand side in the table? With the TAR-200 monotherapy, the 12-month CR rate is dropping then a little bit, which is what we usually see when we treat this kind of clinical situation, 57.4%. Then the 12 months' duration of response, 65.7%, and with a median follow-up of 9.2 months, I think that the number of patients really remaining in response is still a little bit early to be finally assessed.

Also, the TAR-200 intravesical delivery was well-tolerated over time, and the serious treatment-related adverse event rate was only 5.9%.

This is the context here. We have different drugs for the treatment of BCG-unresponsive, non-muscle-invasive bladder cancer. However, in Europe, none of these newer approaches have been approved. The only thing we have in our practice, also in my practice, is gemcitabine-docetaxel combination instillation.

In this context, TAR-200 monotherapy looks very exciting with the three-month CR rate in CIS. The 12-month CR rate with 57.4% looks comparable to gemcitabine-docetaxel as of now in the indirect comparison, of course, but is much higher than with pembrolizumab or nadofaragene firadenovec.

In summary for this abstract, the CR rate with TAR-200 is impressive. The durability of CR and bladder preservation in the long term is still to be confirmed with longer follow-up. The device for delivery seems to be important, but it is dependent on the used drug, and we know that intravesical gemcitabine is active, and this is also good news here.

The second abstract was the AMBASSADOR Study. We saw the extended follow-up data with endpoint disease-free survival results.

The background here is that we have three trials in the adjuvant setting for muscle-invasive urothelial carcinoma: AMBASSADOR, CheckMate 274, and IMvigor 10.

The first two trials with pembrolizumab and nivolumab were positive trials with endpoint disease-free survival, and IMvigor 10 was a negative trial again with disease-free survival endpoint. The inclusion criteria for all the three trials were very similar: high-risk muscle-invasive disease of bladder, ureter, and renal pelvis.

Here we have an overview of some data of these three trials. In the AMBASSADOR in this abstract, we saw the updated results with a follow-up—a doubled follow-up of 44.8 months. Here the data were confirmed, hazard ratio going up a little bit to 0.73 compared to the 0.69 with 22 months' follow-up. These results are still highly statistically significant and very reassuring for the DFS endpoint and here for the ITT population. However, the overall survival endpoint is still immature—not only in AMBASSADOR but also in the CheckMate 274 Study—and IMvigor, as already said, was completely negative.

Now the study landscape in the perioperative concepts is very lively. There is a lot going on. For the cisplatin-fit population, chemotherapy plus IO and new drugs or chemo-IO followed then by adjuvant immunotherapy is basically what is on study. Even more unmet need is there for the cisplatin-unfit patient population.

In these patients, immunotherapy monotherapy or combinations or combinations with new drugs are studied in the neoadjuvant setting and then followed by surgery and adjuvant immunotherapy usually in the adjuvant space.

Here I think it's important to recognize that we are talking about the perioperative therapy concepts and not only about the adjuvant immunotherapy.

Now the last abstract was about biomarker circulating tumor DNA clearance. Here we are in the neoadjuvant space. The VOLGA Trial was studying durvalumab, tremelimumab, and enfortumab vedotin, one of these study arms in the neoadjuvant setting. This triplet had a safety run-in phase, and in this phase, plasma samples were taken at baseline and pre-radical cystectomy or at cycle three, day one.

In this biomarker study, the ctDNA clearance was studied, and what I can show you here is, firstly, the test that was used here was not a DNA-based test, but a methylation-based liquid biopsy cancer test was used.

These kinds of tests can be tumor-specific or can be multiple cancer screening tests. In VOLGA, the Galleri test by GRAIL was used, which is the first commercially available MCED test to detect more than 50 cancer types.

The methylation tests were studied in huge trials and showed to be highly specific—close to 100% in this pivotal publication. The sensitivity was much lower and apparently dependent on the tumor entity and also maybe on the number of patients included.

What I want to point out is here that there are different ctDNA tests: DNA mutation tests and ctDNA methylation tests basically. We need to be aware of the different properties of the tests and need to know in which space we are looking when we use the test and what we want to know from ctDNA methylation tests. We can't expect to get information on actionable alterations, but it is very useful to use when we want to look into ctDNA clearance. So high specificity and the sensitivity may be a little bit less clear.

Let's have a glimpse into the data. In this trial, the data itself were very limited because there were very low patient numbers. It was only a safety run-in phase. Still, I think the data is very inspiring.

What we see here is patients with the neoadjuvant triplet: seven out of ten patients had the ctDNA clearance, and all nine patients that had a pathological CR at cystectomy or a downstaging were also ctDNA-negative pre-cystectomy. I think we can hypothesize how we could use this ctDNA clearance in the future or for future trials, looking into the safety or can we preserve the bladder, for example, when we have a ctDNA clearance? Or can we omit adjuvant therapy when we see a ctDNA clearance?

Also, two patients with a pathologically unchanged tumor had a ctDNA clearance pre-cystectomy, and we could look into the fact if the ctDNA clearance might add information to the pathological results. With that, we could spare patients from a treatment escalation when we have addition to the pathological results. So I think very inspiring data.

In summary, for the three abstracts, TAR-200 monotherapy for NMIBC shows a very high CR rate, low toxicity, and saturation of response still to be confirmed after longer follow-up.

With AMBASSADOR, the update was confirming previous data of adjuvant pembrolizumab. It significantly increases disease-free survival in high-risk muscle-invasive urothelial carcinoma patients in the ITT population. We have rare life-changing side effects, and the overall survival data is still pending.

In VOLGA ctDNA clearance, I think it's important biomarker research, and the methylation tests have a high specificity that might help tailor our treatments.

Thank you.

Alicia Morgans: Thank you so much, Maria. That was incredible, and I think that it's really impressive the way in urothelial carcinoma, every step we take seems to be closer to a world where we can really personalize the approach for patients and give them just the right amount of treatment for a disease that has been traditionally extremely difficult to get through to treat, to hopefully cure for as many patients as possible.

So let's just talk through each of these. I think it's really interesting, the TAR-200 delivery system, which is going to maybe give us an option for treating patients with BCG-unresponsive non-muscle-invasive disease. What are your thoughts in terms of how this is ultimately going to be potentially implemented in clinical practice?

I know you're a medical oncologist, so probably not as engaged in that particular aspect of treatment, but it seems like something that may be really helpful for patients, not necessarily as challenging as instilling gemcitabine and docetaxel intravesically.

Maria De Santis: Yes, I completely agree. I think it's a big advantage for patients because to put a device into the bladder takes only a few minutes, and the patients do not need to lie around on our beds, or turn around and spend hours in our clinics for having the instillation, and then peeing it out. The device stays in the bladder, and we have that continuous drug delivery that is actually not a given and not so controlled when we have the instillations every week, for example.

So I think it is less time-consuming, and usually it's also pretty well-tolerated. We saw the safety data, and this looks really very promising.

Alicia Morgans: Wow. Well, so really looking forward to ongoing work there, as well as in other studies that are trying to support bladder preservation and other approaches, again, to be really as maximally responsive to patient needs as possible.

Now, the AMBASSADOR update—really exciting—and certainly we heard initial results from this study, I believe at ASCO in 2024. But just wonderful to see that that benefit in terms of disease control seems to be sustained and, of course, we're looking to see where things turn out in terms of overall survival.

What are your thoughts in terms of pembrolizumab as another option here for patients, as we already potentially have an option to use something like nivolumab based on the CheckMate Study?

Maria De Santis: I think in Europe we have the special situation that approval for nivolumab is only for the PD-L1 positive population with the TC of 1%. So with pembrolizumab we have an [inaudible 00:15:38] option. I think this is the first important point.

In addition, I think it is important to offer something to the patient to have reassuring data with longer follow-up and to see the patients with a median of 2.4 years until they might have a progression or eventual death. With that, having more than a year without treatment—so it is one year of immunotherapy and more than a year without treatment—so I think this is important for patients.

I know when we have seen in patient-reported outcome data that overall survival is also important for patients, but at least we hit the first bits to improve the disease-free survival for our patients.

Alicia Morgans: Absolutely. In such a high-risk population, this population is always going to be anxious after a surgery—is this going to be enough? Now having the opportunity to do something a little bit more to try to prevent that disease and to show that it actually is effective in doing so is so important for patients.

Maria De Santis: Absolutely.

Alicia Morgans: I agree. To move on to the VOLGA Study, really exciting data here and something that might be applicable, of course, across other studies as we think about these minimal evidence of disease-type assays.

Tell me, what are your thoughts in terms of how this might ultimately be further studied? Because as you said, very small population, something that needs to be replicated, validated. How do you see this being integrated in future studies and potentially clinical care in the future?

Maria De Santis: I think it might really help us to de-escalate treatment to avoid overtreatment, avoid immunotherapy or immunotherapy-related side effects in particular. So I think it is the right way for research and to tailor treatment with a pretty simple test that is kind of a black-and-white test.

This is the kind of test, I think, we really need in this situation. We do not need DNA-specific information, but just see if there is a high likelihood that the patient has no further residual disease.

Alicia Morgans: Great. Well, you know, Maria, you've taken us through a whirlwind of data and given us your thoughts from a really exciting ESMO 2024, particularly when it comes to urothelial carcinoma. I so appreciate your time and your expertise today.

Maria De Santis: Thank you very much, Alicia. It's lovely talking to you. And yeah, let's have the fingers crossed for further new data in the future.