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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Andrea Necchi, who is a medical oncologist at San Raffaele in Milan, Italy. Andrea, thanks so much for joining us again. You've been a great friend to UroToday for many years, and we're looking forward to discussing your ESMO data.

Andrea Necchi: Thank you. Thank you, Zach, for inviting me. Thanks, UroToday, as always, for this activity. I'm really happy to share the data and the thoughts with you today.

Zach Klaassen: Excellent. So we're going to talk about SunRISe-4. The SunRISe platform is really changing trial design and how we're thinking about adding arms to different trials. And this is specifically looking at the TAR-200 mechanism plus cetrelimab in the neoadjuvant setting for muscle-invasive bladder cancer. So maybe just walk our listeners through some of the background and the clinical unmet need in this patient population.

Andrea Necchi: Yeah, thank you. So, as you know, muscle-invasive bladder cancer is a difficult-to-treat disease. It's a deadly disease, with an overall survival rate that is still in the range of 50% after radical cystectomy, with small improvement with standard chemotherapy, with neoadjuvant cisplatin-based chemotherapy. And we are pretty well aware of the limitations of cisplatin in this population. Around 50% of patients are documented to be ineligible for cisplatin-based chemotherapy due to certain renal functional limitations or comorbidities or a decision by the patient not to take neoadjuvant chemo. So there is clearly an unmet medical need. There is a lot of investigation into this. A lot of clinical trials are ongoing today, testing new agents. In particular, they became available after the immunotherapy availability in this disease in the advanced setting. So clearly, we have an important endpoint that is applicable to this type of design, this type of studies—neoadjuvant studies—represented by pathological response. We have uncertainties related to pathological response. We do know that it may be a surrogate for survival in a chemotherapy setting, but there's still a biomarker for this trial to test when testing new agents in these patients.

Zach Klaassen: Excellent. So maybe before we get into SunRISe-4, just review for our listeners the mechanisms of action for both TAR-200 and cetrelimab.

Andrea Necchi: Yes. Cetrelimab is a pretty well-known anti-PD-1 antibody, one of many, I would say, that has been tested in several solid tumors, including non-muscle-invasive bladder cancer, within another parallel study, which is the SunRISe-1 study, with updated data to be presented soon. TAR-200 is a novel way of delivering intravesical chemotherapy. It's a silicone tube that releases gemcitabine through osmotic release. It's important to point out the fact that it may allow continuous exposure of the tumor to the drug, as compared to the intravesical instillation, classical instillation of chemotherapy or drugs into the bladder. This might explain one of the reasons for the peculiar activity of this compound—this tool and the drug—against bladder cancer. This has been developing in several clinical settings and stages in bladder cancer. It is part, for sure, of the SunRISe platform studies.

Zach Klaassen: Excellent. So maybe just walk through for our listeners the study design for the SunRISe-4 trial. How many patients, what were the arms, and the randomization?

Andrea Necchi: Yeah, the SunRISe-4 is the first study reporting data on patients with muscle-invasive disease. In particular, SunRISe-4 includes patients with a diagnosis of T2, T4, N0, N0, pure or predominant urothelial cancer component and muscle-invasive disease. Patients were ineligible for or refused cisplatin-based chemotherapy. So they were part of the 50% of the cisplatin-ineligible population. The study consisted of two parallel arms. It was a randomized study, but it was not a comparative study. It was a parallel study testing the combination of TAR-200 and cetrelimab every three weeks for four cycles before radical cystectomy or cetrelimab monotherapy. So immune checkpoint inhibitor monotherapy, four courses every three weeks before radical cystectomy. The primary endpoint was the pathologic complete response rate, defined as the lack of any residual viral disease at the time of radical cystectomy. And there were, of course, a lot of secondary points, including pathological major response to non-muscle-invasive disease, relapse-free survival, safety, and future biomarker analysis.

Yeah, the study is planning to randomize about 160 patients. The design is pretty complex, but in fact, the study is aimed at including around 100 patients in the combination therapy arm and 60 patients in the monotherapy arm. The data that were presented at ESMO this year were relative to the second interim analysis, counting about 80 participants—50 patients in cohort one (the combination therapy) and about 30 patients in cohort two (monotherapy with cetrelimab). So in particular, among these patients, we reported on the efficacy-available patients, which included 53 patients in the combination therapy arm and 31 patients in the monotherapy cetrelimab arm.

Zach Klaassen: Outstanding. So walk us through those key results from this second interim analysis for SunRISe-4.

Andrea Necchi: Yeah. Let's jump directly to the interim results of the primary endpoint. So the pathological complete response with the combination therapy was 42% in the ITT population and the efficacy-available population. And with the pathological objective response defined as the presence of residual non-muscle-invasive disease of 60% in the combination therapy. Conversely, in the monotherapy arm, the PCR rate was 23%, so about one-half of the PCR rate reported with the combination therapy, and the pathological objective response was 36%. It's important to say that this study and the randomization within this study were stratified based on two particular clinical factors: clinical T stage (T2 versus T3, T4) and completeness of the TURBT prior to study neoadjuvant therapy. In fact, when looking at these two different cohorts of patients, we realized that the pathological complete response in clinical T2 patients rose to 48%, with an objective response of 68%. And interestingly enough, in patients with incomplete TURBT prior to starting treatment, the PCR rate was 56%, so in the same range as patients who started with a complete resection of the tumor. So this further applies to the potential efficacy of this combination therapy, in particular of the intravesical therapy, and potentially overcomes the limitations of the radicality of TURBT, which is one of the known concerns when dealing with PCR results in any neoadjuvant therapy trial.

Zach Klaassen: Yeah, that's exciting data. No question. So I think you mentioned off the top that 50% of people may be cisplatin ineligible. Just speak to the potential benefit of having an intravesical therapy and a systemic therapy that doesn't depend on cisplatin eligibility.

Andrea Necchi: Yeah. One of the most important impacts this kind of approach may have is related to safety. The safety profile of the combination therapy was really mild, with only a limited number of grade 3–4 side effects. If you compare this data with systemic combination therapy data, or even with systemic combination immune therapy data, that could be an advantage for sure. Particularly if we consider that we are dealing with a frailer patient population that usually has impaired function and a lot of comorbidities. So this is a difficult-to-treat population, almost impossible to treat with standard chemotherapy. This is one of the most important findings.

Another finding, secondary to the safety profile of the combination therapy, is related to the fact that if you see the data related to the exposure of TAR-200 doses to the patient, you see that patients who were able to complete the four courses of TAR-200 benefited with up to 50% pathological complete responses, with an objective pathological response rate that rises to almost 70%. This means that there is still, for sure, a safety point here. And there is another important point related to the learning curve of urologists in dealing with this kind of device and this kind of tool, and providing patients with the best approach and best management of this treatment.

Zach Klaassen: Excellent. So you mentioned there are about 80 patients now; we're hoping to get to 160. When do we expect to see full accrual and some additional data beyond the ESMO presentation?

Andrea Necchi: Yeah, the trial has accrued very fast, as all the trials in the SunRISe platform, I would say. So the trial is expected to conclude enrollment by the end of the year. I think that in Q1 next year, we will be able to present updates from this trial in terms of the primary endpoint and secondary endpoints, and maybe also biomarker data.

Zach Klaassen: Wonderful. Always great to chat with you, Andrea. Maybe a couple of take-home messages for our listeners today?

Andrea Necchi: Oh, the first message, maybe one of the most important messages to provide based on this data, is that we may have for the first time an intravesical and systemic therapy combination to provide to patients diagnosed with muscle-invasive disease. This corroborates the need for a multidisciplinary approach to the disease, still involving urologists and medical oncologists together to treat these patients. The second point is related to the tolerability and educational needs that this trial highlights, particularly when dealing with the best management of TAR-200 in these patients on a daily basis, and allowing as many patients as possible to receive the four courses of the drug.

Zach Klaassen: Outstanding. Andrea, thanks very much for your time, expertise, and for sharing the data from SunRISe-4.

Andrea Necchi: Thank you. Thank you, Zach. Thank you, UroToday. I really appreciate it.