Today we're going to hear about a very interesting, exciting new paradigm that people are exploring and that was presented recently, the use of Urinary Tumor DNA-Guided De-escalation of Systemic Immunotherapy in Extensive Very-High-Risk Non-Muscle-Invasive Bladder Cancer. So looking forward to hearing what you have to say.
Yunkai Qie: Okay, thank you. Dear Dr. Kamat, Angela, and other UroToday audience, it's my great pleasure to share our research with you here. Our work centers on utDNA guided deescalation of systemic immunotherapy for intensive very high-risk non-muscle-invasive bladder cancer. On behalf of our principal investigator Professor Hailong, who and all members of our team, I will draft my presentation into three sections. First, the clinical background of systemic immunotherapy for NMIBC. Second, our study design and the clinical challenge we aim to address. And finally, our future research plans.
Let's start with the background. Systemic immunotherapy is now used to treat in NMIBC. Landmarks chose such as KEYNOTE-057 and SWOG-1605 initially focused on BCG refractory patients. Later studies including CREST and POTOMAC expand the ablation to BCG-naive populations. These regimens have demonstrated promising efficacy but also accompanied by awareness treatment related adverse events.
Again, this background, we launched the oral phase II TRUCE-2 trial, which target a special group of patients with extensive very high-risk NMIBC. We treated them with Tislelizumab and Nab-paclitaxel. With the completion of these drugs, the region achieved high risk of complete response and duration of response and PFS. However, we also observed a high incidence of treatment-related toxicities. These risks critical questions for patients who achieved CR and preserved their bladders, do we need to stay in systemic immunotherapy indefinitely? Can we discontinue the treatment? If so, when and who? So what's really going on here?
When we further analyze these CR patients, we found their treatment courses varied greatly, ranging from 3 to 17 cycles. Interestingly, patients who received six cycles of fewer achieved comparable clinical outcomes to those who had more than six cycles. Therefore, we put forward two key questions. Do our CR patients really require long-term systemic immunotherapy. And how can we accurately select patients who can safely stop unnecessary prolonged treatment?
To answer these questions, we turned to utDNA highly sensitive biomarkers for detecting local rescue license. We hypothesized that clinical CR alone is not sufficient for treatment guidelines and utDNA-based molecular response assessment could help us implement treatment deescalation.
We continued to enroll patients with the same inclusion criteria and treatment protocol. After patients obtained TURBT confirmed CR, they received the three additional cycles of therapy. Following by assessment, risk assessment, were cytoscopy and the biopsy. For patients who maintain sustained CR, we performed the utDNA testing. A total of 54 patients were confirmed the utDNA negative. Still divide 21 with short-cycle and 33 with long-cycle.
Our findings validate our hypothesis with media follow-up of 42.8 months. The two groups had a similar recurrence-free survival with six recurrence events in the short-cycle group and eight in the long-cycle group. Regarding radical cystectomy-free survival, we recalled 5 cystectomy cases in short-cycle group verse two in the long-cycle. Notably, only two patients in the short-cycle group and one in the long-cycle group received a radical cystectomy due to disease progression to muscle invasive bladder cancer. Most remaining cystectomies were based on physician's clinical judgment and the patient's personal choice. This result clearly proved that utDNA negative can reliably identify candidates for treatment deescalation without compromising a long-term survival.
More importantly, short cycle therapy leads to far fewer overall adverse events and graded three to four severe toxicities showing a much better safety profile. In short, a utDNA negative is a reliable indicator to screen patients eligible for immunotherapy deescalation.
Beyond these encouraging results, we have launched multi-center randomized trial named TRUCE-LB03 to further validate this utDNA guided strategy. Its primary endpoint is bladder intact event-free survival.
To conclude, utDNA is a valuable non-invasive tool to support personality immunotherapy escalation for extensive very high-risk MIBC. This strategy effectively balanced the treatment efficacy and the safety. We are looking forward to the outcomes of our ongoing utDNA related trials for MIBC.
Okay, thank you all. Thank you, the patients. Thanks for your attention.
Ashish Kamat: So thank you very much for that presentation.
Yunkai Qie: Thank you.
Ashish Kamat: One of the questions that we often get asked and we think about when it comes to utDNA is first off, was it tumor-informed or tumor uninformed utDNA? Could you tell us a little bit about the actual platform that you used?
Zihan Xue: So the assay we used in this study is tumor naive. Assay. So actually, we did not based on the tumor tissue testing sequencing. So it's tumor-naive assay and we use the low coverage WGS tumor naive. It's a whole chromosome utDNA test.
Ashish Kamat: Great. So since you used a tumor-naive utDNA, did you also then compare its performance with standard assays, for example, routine cytology and/or the UroVysion FISH assay that looks at the chromosomes 3717 and 9P deletion? Did you look at those, as well, and see if they performed in a similar manner?
Zihan Xue: Yeah, in this cohort and actually during all our clinical trials, we always basically do the all mainstream uroliquid biopsy. And we did the cytology, we did the MP22, we did the FISH, actually, and we did the whole chromosome utDNA testing. And of course, I think we did not disclose this findings in oral presentation, but I can tell you that it's way better than the cytology in its sensitivity, of course, and the sensitivity shows superior to the standard FISH.
Ashish Kamat: Do you remember or know offhand how much better the utDNA was compared to, say, the FISH assay?
Zihan Xue: I think its superiority shows more than 15% utDNA sensitivity, more than 15%.
Ashish Kamat: And the reason I ask that, of course, is utDNA, when it is tumor specific, it might be one particular strength of the assay. The tumor non-specific also is very important, of course, because as we know, bladder tumor recurrence is a field effect and you might be picking up field changes. So both have very valid reasons to be used in different scenarios.
Now let me ask you another question. In your treatment, because we focused here on the utDNA part of it, but the treatment is fascinating, as well. So with the newer treatment paradigms that we've seen, the recent approvals in the US, and of course I know that you are working on several agents, as well, how do you think the systemic immunotherapy agents will fit into the overall treatment paradigm for patients?
Zihan Xue: So it's difficult to treat all the NMIBC patients with identical regimen. So for this patient, for this cohort, for this population, it's really, the tumor is very extensive and cannot be structurally resected at a single time. So we initiate this systemic immunotherapy strategy for the population with this kind of tumor.
Ashish Kamat: And I was going to ask, outside of the clinical trial, what is your current treatment paradigm for these patients? What do you offer these patients outside of the clinical trial?
Zihan Xue: First, we would recommend doing the radical cystectomy first because they are a very high-risk tumor and many of them cannot do the TURBT completely and we would recommend the RC first. But of course, many of them just refuse to do the RC surgery. So we would recommend doing the systemic immunotherapy. But based on the HER2 expression, we also initiate another strategy. We use the RC-48, which is the HER2 ADC plus the immunotherapy, which is the Tislelizumab. That's another strategy. And Tislelizumab and Nab-paclitaxel, which we showed in this presentation is another strategy.
We can't say which one is better because we did not run the head-to-head study. So I think the non-surgical strategy for this population is quite limited.
Ashish Kamat: No, great. Exciting work, of course, and looking forward to seeing what the prospective study shows. Has that study opened already? Where are you as far as the prospective ongoing study is concerned?
Zihan Xue: We are enrolling patients right now in many centers in China.
Ashish Kamat: Excellent, excellent. So once we have the results of that, we would love to have you back here to talk about it. So congratulations.
Zihan Xue: Thank you so much.
Yunkai Qie: Thank you so much, Dr Kamat.