Ashish Kamat: Hello everybody and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas. And joining us once again to talk about his ESMO presentation is Professor Andrea Necchi. Andrea, you were everywhere at ESMO and you also presented SunRISe-4, which you've been very involved with in the past here. Your presentation was primary analysis and biomarker results and a lot of us were waiting with bated breath to hear what you had to say. So thank you for joining us and take it away.

Andrea Necchi: Thank you Ashish, and thanks UroToday for the opportunity. Yes, we have presented this ESMO meeting this year, the primary results, the final results of SunRISe-4, the interim results of this study, neoadjuvant gemcitabine intravesical system, plus the cetrelimab or cetrelimab monotherapy before cystectomy in MIBC in patients who are refusing or ineligible to stand a neoadjuvant chemotherapy. The interim results, as you remember, are being recently published in Lancet Oncology and presented the last year at the ESMO meeting. Here will present the final results and the biomarker circulating biomarker results. The standard of care and is pretty much known to be radical cystectomy upfront for patient who refuse to receive cisplatin-based chemotherapy or chemo radiation is also there for patient like this one, the prognosis is still suboptimal, so there is a need for implementing the outcomes by testing newer therapies, newer and better tolerated therapies as compared to chemotherapy combinations.

And there is a need for improving the compliance of treatment by ending well tolerated treatments in short-course neoadjuvant therapy. I mean perioperative approaches in these patients. The design of SunRISe-4 is pretty well known, already presented and published. So a patient with clinical T2-T4a and 0M0 MIBC with a predominant or pure urothelial carcinoma histology ineligible for or refusing cisplatin chemotherapy were enrolled and randomized to receive gemcitabine intravesical system, formerly known as TAR-200 in combination with cetrelimab or cetrelimab monotherapy for four cycles every three weeks before radical cystectomy. The primary endpoint of this study was a pathological complete response rate and there were of course a plethora of other secondary endpoint and in fact, part of the endpoints in particular the exploratory biomarker analysis, focused on the utDNA, urinary tumor DNA or ctDNA circulating tumor DNA, minimal residual disease assessment that had been presented this year.

Patient characteristics in the final population are pretty much similar to many other studies of this kind. The vast majority of the patient presented because of the fact that they refuse chemotherapy not due to ineligibility of chemotherapy. This is an intriguing point. There was no major disconnection between arms with regards to the patient baseline characteristics, performance status, clinicality stage, the vast majority of the patients, 78% in cohort one 84% in cohort two presented with clinicality two disease and a few patients had received prior to TURBT and intravesical therapy for non-muscle invasive disease. Around 20% of the patient in both arms presented with visibly residual disease judged by the local investigator prior to start neoadjuvant therapy. The final results are shown here on the study. On the left-hand side you see the pathological response rates. With the third one, the denser trial amount, CR rate was 38%.

Pathological down-staging rate was 53% with cetrelimab monotherapy, the rates were 28% and 44% respectively. On the right-hand side, you see the first survival outcomes in terms of relapse free survival and you see that there is an improvement in the 12 months of relapse free survival rate. In the combination of therapy arm 77% as compared to 64%. The study was not powered for testing any kind of improvement, formal improvement, statistically significant improvement in survival. There is an incremental improvement in this descriptive analysis. No new safety signals have been recorded during this analysis.

The drug TAR-200, cetrelimab, confirmed to be pretty well tolerated. If you see the column grade three four side effects, they were all below the 10% rate. The treatment rate adverse event and serious adverse events were pretty much in line with previous publications and the previous presentation. Regarding the utDNA MRD assessment. The results of the combined codes are shown here, 82% presented with utDNA positivity baseline and at 12 months, so after the neoadjuvant treatment, the utDNA positivity fell to 52.3%.

There is no disconnection, there is no difference between arms with regards to the utDNA data. Interestingly enough, there is no difference with regards to utDNA positivity between patient presenting with visible residual disease or with a complete resection of the tumor. The utDNA positivity tested as high as 81, 82% baseline in those with the complete resection of the tumor and 83% in those with incomplete resection of the tumor, corroborating the fact that the completeness of the TURBT could not be necessarily a way of biasing the results of pathological responses. The utDNA negative status at week 12, so after treatment was clearly associated with pathological complete response, 81.5% of those who achieved a Path CR were utDNA negative at week 12 as compared to 21% of those who did not achieve a Path CR. In the oncoplot. Here it is clear that there is an enrichment in the red bars indicating the negative utDNA status in the Path CR subgroup.

Also in the 30 patients who had the possibility to have analysis of match pre and post utDNA, [inaudible 00:06:52] patients overall in the two arms, there is the possibility, there was a possibility to look at the clearance of the ctDNA and 80% of the patients were utDNA positive baseline and achieve the Path CR and the utDNA clearance at week 12 as compared to only 13.3% who did not achieve a Path CR. So also utDNA clearance was associated with Path CR and this is also shown here in the oncoplot on the upper side. Regarding ctDNA. ctDNA in this study confirms previous findings from other studies and other major studies also presented at this year's ESMO meeting.

Relapse free survival was clearly different in patients presented with baseline ctDNA negative status as compared to positive status. And also on the right-hand side here, relapse with survival was clearly different for those who had a ctDNA positivity at week 12. So post-neo-adjuvant therapy pre-surgery as compared to with those with still positive test. And interestingly, week 12, ctDNA MRD status did not correlate with the pathological complete response outcome.

So at the primary analysis, the final analysis of this study, TAR-200 and the cetrelimab confirmed to be an effective combination therapy, warranted further investigation, maybe in randomized study, maybe towards newer standard of care that are emerging in this field. Also, relapse free survival is presented for the first time, it is quite promising in this patient population. And interestingly, the biomarker story here is indicated that ctDNA and utDNA are both useful in this patient population. utDNA more for the interim endpoint of pathological response, ctDNA for the long-term endpoint of survival.

But these two endpoints are very much useful when envisioning new strategies, maybe your bladder sparing approaches when looking at the possibility of sparing the bladder, any kind of radical local treatment, utDNA is maybe for one of the first time presented here in this study on one of the strong biomarkers or one of the strongest biomarkers to be integrated in a neoadjuvant therapy strategy for this patient population. So again, it is a huge effort here, multi-country effort. So the effort, a huge contribution by the patient, their family, their caregiver, supporting staff investigators from the sites and, for sure, Johnson & Johnson for supporting the study. Thank you.

Ashish Kamat: Thank you so much, Andrea. And once again, congratulations. We were all looking for biomarkers and ability for us to use correlates to actually correlate with Path CR because ultimately as you have been championing, we would all like to not take out bladders, right? So we are looking at markers that will help us predict... Going back 20 years, 25 years, cytology has in the past been a good correlation between what we see and pathologic complete response, right? Because if there's no tumor present in the bladder, there's no positive cytology and of course now as technology is involved, we're using utDNA. But in this study, did you explore just routine cytology or UroVysion FISH or one of the existing markers? And if so, could you shed some light on how that correlated with Path CR?

Andrea Necchi: Yeah, great point. Actually was not included as part of the assessment of this study. The conventional cytological assessment was not included in this study. I agree with you. I agree with you that we could start from what is existing already and then maybe compare utDNA data with what is existing. I have a very bad experience when using, within trials or routine practices, cytological assessment in the urinary tumor, urinary cytology assessment because of the fact that there is a huge heterogeneity in the way the pathologist assess the urine for this feature. And we have a lot, quite a lot of these in my now experience, quite a lot of negative cases that turn out to be positive cases when reassessed locally. So with centralized assessed, it's very much operator dependent, very much the pathologist dependent. So the possibility to have a technology put here when analyzing urine instead of men looking at the urine samples is a great thing.

In particular, as you mentioned, when envisioning the possibility for putting this biomarker in the decision-making process of saving the bladder and I think that if confirmed with larger numbers. I think that we are pretty much in line with the story, with continuation of the story that we built with the consensus criteria for clinical CR, for the bladder preservation, because we could put here an additional piece in the puzzle for the bladder preservation after neoadjuvant therapy depending on the response to treatment by integrating the clinical data, ctDNA data, utDNA data.
And so the data is very much interesting to me, and in particular the combination of the two, utDNA and ctDNA, and the different performance of these two biomarkers in the different endpoints of the interim endpoints for pathological response and the long-term endpoints. So they seem to be perfectly interchangeable, integrated in a unique strategy. This is a good thing for us, for the healthcare system, for the patient first and so it's pretty much exciting.

Ashish Kamat: Yeah, no, I agree with that. I think what we've learned over the years is that when you get a CR, whether it's derived with single therapy, monotherapy, however it is, that does correlate better with patient outcomes. I think that's the ultimate goal in a CR. If you can identify clinically as you've shown in your JCO paper, right? I mean, that is a good way to serve as a biomarker and a surrogate marker. So I think that's excellent. Andrea, again, congratulations on all your activity at ESMO. Always a pleasure to see you. Thank you for taking the time.

Andrea Necchi: Thank you, Ashish. Thank you and UroToday for inviting me. Thanks.