Andrea Necchi: Thank you, Ashish. Thank you for the invitation. Thank you, UroToday.
Ashish Kamat: So again, you're doing a lot of stuff here at GU ASCO, as you always do, a lot of stuff here for us at UroToday. What I'd like you to focus on now is summarizing the data from SunRISe-2 that you're going to be presenting.
Andrea Necchi: Yeah. SunRISe-2 is a phase III trial, it was a big endeavor, in patients with muscle-invasive bladder cancer. The trial was a randomized phase III study aimed to compare two different approaches to treat patients with bladder cancer and sparing the bladder. The trial included patients with clinical T2, T4a, N0, M0 MIBC with pure predominant urothelial carcinoma histology, ECOG PS 0-2 who were refusing or being unfit for radical cystectomy. The patients first underwent re-TURBT, radical re-TURBT, as the first trial-related procedure during the screening phase, and then were randomized to receive, in arm A, TAR-200, formerly called TAR-200, now Gem-iDRS, gemcitabine intravesical system, plus cetrelimab for a total period exposure over 144 weeks, or chemoradiation as a standard of care with either a conventional dose or hyperfractionation using either gemcitabine or cisplatin as a chemosensitizing agent depending on the investigator decision. The primary endpoint of the study was a bladder-intact event-free survival. There were key secondary endpoints including overall response rate, metastasis-free survival, overall survival, and safety.
The results were stratified based on the re-TURBT outcomes, completeness or not completeness of re-TURBT, and the clinical stage assessed at the re-TURBT, so T0 versus residual non-muscle-invasive disease versus T2 or higher stage. The trial was conceived in September 2020. The futility analysis was planned after the initial 300 patients enrolled. The initial plan was to enroll and to randomize 550 patients. There was a futility analysis, as I said, after the initial 300 patients achieving the week 18 overall response rate assessment. And based on the futility analysis that occurred in July 2024, the IDMC recommended the study to be stopped, looking at the overall response rate and the totality of the data including BIEFS, MFS, and OS. So in September 2024, the study and enrollment and randomization were concluded after 518 patients randomized. Then the protocol was amended with the late extension phase, allowing patients in CR, in arm A with the Gem-iDRS and cetrelimab, to continue the treatment until the end, and all patients were randomized in the chemo radiation arm to complete the treatment until the end. So we presented here at the meeting the results of the final cutoff analysis that occurred in July 2025. That includes the final safety data and exploratory long-term BIEFS data or our MFS and OS.
The population of patients randomized was pretty much consistent between arms. It's important to underscore the fact that 30% presented with ECOG 1 or 2, so a pretty frail patient population. 44%, 38% in the two arms presented with a T0 stage at the re-TURBT. The majority of patients received a conventional-dose radiation, and the majority is cisplatin chemotherapy. The overall response rate, which was one of the key endpoints in this study, and the CR rate, in particular, were similar between arms, around 50% in both arms. And the BIEFS, bladder-intact event-free survival, in patients with CR were fully overlapping, the curve both fully superimposing between arms. In the intention-to-treat population, BIEFS was numerically higher in the chemo radiation arm. The 12-month projection of the BIEFS for chemo radiation was higher than 70%.
Ashish Kamat: So Andrea, let me ask you here a quick second. Don't want to interrupt you, but were you surprised by that?
Andrea Necchi: Partly, yes. For sure in this trial, the chemo radiation arm outperformed as compared to the initial plan and as compared to the chemo radiation data reported in the big trials conducted in the past. This is a big trial. Around 250 patients were randomized to the chemo radiation arm, so one of the biggest chemo radiation trials conducted in the history of patients with MIBC. The reason why the data are so good for chemo radiation, as with the Gem-iDRS and cetrelimab, the same, are difficult to conceive. Many things may happen. For sure there is an impact of radical TURBT, the quality of the TURBT that is systematically performed before randomization, that may have affected the outcome of the patients. It's interesting to see, if you look at the shape of the BIEFS curves in the ITT population, you see a drop of the curve at the week 18 assessment, corresponding to the clinical response assessment, and then the curve becomes flat, meaning that the patients who get a clinical complete response, patients who are complete responders to both strategies maintain the disease-free status at the long run. It always depends on what is happening at the short run with initial response.
This is good for the patients overall, but put into question to myself, and I admit I have difficulties in fully conceiving the role of chemo radiation today with regards to the developments of perioperative therapies, because it's the first trial testing newer strategies against the other standard of care, which is not cystectomy, but chemo radiation. And the first trial failed, actually, to meet the primary endpoint. It's an important point to make when considering the next steps, in particular when looking at the newer data from EV pembrolizumab for the most effective strategies provided into a surgical approach.
Ashish Kamat: Absolutely. Andrea, again, I want to probe you a little bit on that. Because again, the way the trial was designed, yes, you have to say it was stopped, it was futile, it failed to meet its primary endpoint, but do you really think that we don't have sufficient data from this to suggest that the Gem-iDRS can still be part of this?
Andrea Necchi: I think that there is a growing proportion of patients who may not need or who may refuse chemo radiation, radiation therapy, as with radical cystectomy. So it's interesting to realize, at least in my reality, that it is not necessarily mirroring what is happening in real world, but the profile of the population of patients who, at a certain point in time, particularly after response to any kind of systemic therapy, raise the bar of the success saying, "Okay, doctor, I don't want just to be cured, but be cured potentially without any major side effect of the long run or the short run due to an intense bladder-oriented approach." So there is a parallel refusal for cystectomy and chemo radiation at a certain point in this population. And you have data suggesting that with Gem-iDRS and cetrelimab, you can provide at least similar data in this patient population by limiting maybe the long-term effects of radiation therapy that we were not able to capture in this study because the median follow-up time was just 11 months, so most of the long-term sequelae of chemoradiation have not been captured in this readout.
So I think that there is an opportunity to escalate a little bit the program by looking at novel intravesical therapies as a way of consolidating response in the context of use of newer therapies perioperatively by sparing a little bit at the intensity of treatment. So this is an opportunity, but for sure what we know from other bladder-sparing trials is that the rate of intravesical relapses by using systemic therapy alone is concerning and intravesical relapses may anticipate metastatic development. So using something to consolidate the response into the bladder or directly to the bladder tumor may be good enough. And this way, I think that there is still an opportunity to look at TAR-200 and immune therapy or TAR-200 in clinical stages, which is a bit higher, a bit more advanced as compared to the current label, to the current approval of TAR-200, which is in the CIS population.
Ashish Kamat: Correct. And again, we have to talk about approved, but scientifically it makes perfect sense, right? And even though this trial read out as negative, and again, kudos to you and everyone else that was involved in it for actually embarking on this study, I think we've learned a lot from this. Andrea, again, always a pleasure having you here, looking forward to seeing what you do next, and thanks for taking the time.
Andrea Necchi: Thank you for the invitation. Thank you.