Alex, it's always a pleasure to have you on board.
Alexandra Masson-Lecomte: Hi, Ashish. Thank you very much for the nice introduction, and thank you for giving me the opportunity to present a little bit this STARBURST project that I care very much about, which is about defining clinical complete response after systemic therapy in muscle invasive bladder cancer. So, I'll spend just a few minutes explaining a little bit of the rationale of the project and then a few slides showing you exactly what it is about.
Here it is. In the past 10 years, we really have fully entered the era of neoadjuvant treatment in muscle invasive bladder cancer. I would have said neoadjuvant chemotherapy previously, but as most of us know, it's now about chemotherapy, but also combination of treatment with immunotherapy and potential new therapies that are coming. So, with all those new treatments, the rate of patients with complete response on the radical cystectomy specimen has raised from 4% to 10% in 2014 to around 40% in 2024.
The part of us that are seeing the bottle half empty are saying that when you get a complete response on a radical cystectomy specimen, it is an excellent news for the patients, as they are most likely cured, which is true. But if you see the bottle half empty, you might consider that we are removing more than half of the bladder for nothing, since there are no pathological tumor remaining on the radical cystectomy specimen, and so we might be seeking for alternatives for those patients.
However, there are several major issues to be solved if you want to be able to offer some game-changing strategies, some different treatments to our patients that are complete responders. And so as a community, we need to agree on how to define complete response. Is it a patient with no tumor? Is it the patient with a non-muscle invasive tumor? What about CIS? Is it TA [inaudible 00:02:23] T1? This still needs to be defined. We also need to decide how to assess response after neoadjuvant treatment. We have a bunch of different tools. I'll show it on the next slide, but there is no standard of care reassessment after neoadjuvant treatment. And if we want to change practices, we need to be able to build powered enough phase three clinical trials and trials that are designed in a population of all comers and not only patients that are refusing or ineligible to standard of care radical cystectomy, which is the case of most phase two trials that have been conducted yet.
So, the tools available for response assessment go from cytology, cystoscopy, TURBT, which are very well-known clinical tools that we're all using in our daily practice, to new imaging with MRI. That is not so new in bladder cancer, since we have been starting to use it for a few years now, but it's not a standard practiced in all the centers. And also, some new tools, much newer, such as urine and circulating tumor DNA that are very interesting in following up the patients, but also potentially assessing response to treatment. We have seen it in the NIAGARA trial. And also, multiplexed urinary markers that are being developed in non-muscle invasive bladder cancer, mainly for the diagnosis and follow-up, but that also might be useful in the setting of assessing response to neoadjuvant treatment.
So, those are the grounds on which we are building the STARBURST project. This project that we have described and published in European Urology is divided in two phases. The first one, which is called STARBURST-1, aims at building a cohort to define a complete response signature. So, this is a cohort of patients, all comers with muscle invasive bladder cancer, not especially selected T2 to T4, N0, N1, no metastasis, urothelial cancer that are eligible for neoadjuvant treatment standard of care, neoadjuvant treatment followed by radical cystectomy.
And what we intend to do in this study is to assess the patients before and after neoadjuvant treatment with a bunch of different tools, cystoscopy and biopsy or TURBT if it is a standard of care in the center, plus MRI, cytology, circulating tumor DNA, urine tumor DNA, as well as multiplexed urinary markers. And all this assessments, all those tools will be repeated three to four weeks after the neoadjuvant treatment before the radical cystectomy. So, it's not a question of doing or not radical cystectomy. All the patients will have the cystectomy, since the end point will be the pathological response on the radical cystectomy specimen. What we really want to do here is to be able to identify markers that have a high sensitivity in detecting muscle invasive disease after neoadjuvant treatment.
So, this is the first part of the trial. And we aim at including in this part of the trial 220 radical cystectomy patients. The second part, provided we are able to validate the tools we're now using, some of us in daily clinical practice to reassess patients after neoadjuvant treatment, is about building phase three trials, phase three clinical trials for de-escalation strategies in the patients that are responding to neoadjuvant treatment and escalation strategies in the patients that are not responding.
So, the trial begins the same as the STARBURST-1 project. The patients that are eligible for neoadjuvant treatment undergo an evaluation with cystoscopy biopsy, MRI markers. I don't know exactly. We will define it with STARBURST-1. They are reassessed after neoadjuvant treatment. And in case they are defined as complete responders, then they would be offered some de-escalation strategies. And there are multiple possibilities, so this is why we have designed a trial that is called TWiCS, which is trial within cohorts. This allows the investigators to conduct multiple cohorts in parallel, since in those responders we could consider active surveillance, experimental drugs, experimental and transvesical device, radiation therapy. There are multiple options. On the contrary, if the patient is not responding, we know that the prognosis is really bad in this situation. We might consider escalation strategies for those patients with potential new systemic treatment intensification before radical cystectomy or alternative treatments.
So, this is where we are heading. We are very far from being able to conduct the TWiCS, as it is presented on the slide. There are still multiple questions about endpoints and follow-up. The kind of endpoints we are using in clinical trials might not be applicable to complete responders, since those patients have excellent prognosis and there is a lot of work to be done. But I really hope that as a community of urologists, radiation oncologists, and oncologists that are treating muscle invasive bladder cancer patients, we are able in the future to head to that and be able to treat the patients according to response.
So, here it is. Thank you very much for the opportunity to present the project.
Ashish Kamat: Thank you so much, Alex. This is a very important project, as we all know, and congratulations to you for spearheading this. Do you have an idea as to how many sites you might be asking to enroll? Can anyone listening in here, if they belong to the EORTC, approach you? How can someone participate in this if they want to?
Alexandra Masson-Lecomte: Yeah, absolutely. So, for the STARBURST-1 project, it's a rather small trial, since it's 200 patients treated with standard of care. So, we are planning to conduct this within the EORTC network probably only in Europe. We will be selecting the centers mainly in France, Italy, Spain, Belgium, but we will send a survey to all EORTC centers to seek whether they want to participate. And some have already contacted me to ask me about it. So, if some of the urologists and oncologists that are listening would be happy to participate, they can obviously let me know. But if they are in the EORTC network, they will be contacted.
Regarding the TWiCS trial and the further cohorts, this is still a plan. We still have no clinical trial that is built. And this will obviously have to be multi-center, multi-continent. It will have to be conducted in Europe, but also in the United States, South America, Australia, and so we will, again through the EORTC network, but also through all the other research network that we have been working with, try to find centers in each of the countries.
Ashish Kamat: Yeah, and this is something, like you said when you started, this is something we're facing every day in clinical practice. And that's why the IBCG, which of course you are a member of, we had a retreat last year in Milan and put together people from the FDA, from EMA a think tank. And in fact, it's September 10 today, and tomorrow, September 11th, our publication is going to come out in JCO that outlines exactly the paradigm, our recommendation as to what you consider CCR, what you do, which tools to use, et cetera. And I think obviously since it's embargoed right now, but once it's out, I think you'll be pleased that a lot of our recommendations are already incorporated into your trial, so again, congratulations for thinking ahead.
This is so important that, in fact, next year we're going to have a similar retreat focusing on how to implement this in the real world because, while we absolutely need clinical trials, patients are still coming today and saying, "I think I have a CCR. I don't want my bladder out." And we really need to know in today's day and age with what we have with the incoming of EV-Pembro, obviously with EV-302, 303, 304, how are we going to address these patients? So, let me flip it away from the trial a little bit, Alex, and ask you in your clinic today, how do you use these tools? Do you need a completely clean MRI, a little thickening on MRI? Is that okay if the biopsy is negative? How do you put all this together on how to counsel a patient that's sitting in front of you today?
Alexandra Masson-Lecomte: So, in my practice in my hospital, we reassess all the patients after neoadjuvant treatment. But since this is not standard of care and we are not doing this in a clinical trial, since the clinical trial does not exist, we try to be very stringent on what we consider a complete response. So, to consider a patient a complete responder, he or she has to have a normal TURBT, meaning no residual disease, not even non-muscle invasive, so no residual disease on TURBT, and normal MRI.
So, for now, this is what we are using. If the patient reaches those two criteria, we offer alternatives. So, some go to radiation therapy, but there are even some patients that go to active surveillance in case the tumor was small and completely rejected. And this is still a discussion with them. But what we consider a complete response is a patient with no residual tumor. However, I always feel a bit uncomfortable when I find a small non-muscle invasive residual disease to say, "Well, you absolutely need a radical cystectomy," because I know that if I do a TURBT, then my patients will be T0. If I do the cystectomy and I just get a small one-centimeter TA high grade, I can also question myself whether the radical cystectomy was really necessary.
But this is exactly what STARBURST-1 is about. We want to be able to identify the populations of patients. There are the complete responders, what we could call the near-complete responders, the non-responders, even the progressing patients, all those categories of patients might deserve different kind of treatments. But this is still an open question.
Ashish Kamat: Right, absolutely. And that's why I think doing a trial like this is very important. And I'm sure once you have all the data, there'll be ways, machine learning otherwise, in which we can even refine the criteria to more than what we as clinicians can see with the naked eye.
Alex, once again, thank you for taking the time. Really excited about this study. Congratulations.
Alexandra Masson-Lecomte: Thank you very much, Ashish. Bye-bye.