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Ashish Kamat: Hello and welcome to your today's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center in Houston. And it's a distinct pleasure to welcome to the forum again someone who really needs no introduction at this point, but I'll introduce him anyway. Professor Andrea Necchi is a dear friend of mine. He's also a true expert in the field of bladder cancer, immunotherapy for bladder cancer. And today, he's going to present to us his data on the VI-RADS system, and how it correlates with the pathologic and molecular outcomes of patients that are undergoing perioperative IO therapy. So Andrea, the stage is yours.

Andrea Necchi: Thank you Ashish. It's a great pleasure to be here again. And thanks to UroToday people for allowing me to present to you and to highlight our analysis that we presented at AUA this year. It is related, as you mentioned, to the evaluation of VI-RADS. So MRI data, with regards to response to neoadjuvant Pembrolizumab, within the PURE-01 study. These are my disclosures. So as a background, as you know, the staging and response evaluation of muscle invasive bladder cancer has been characterized by limited possibilities historically, with the use of either CT scan or PET-CT scan or MRI. But of course, in principle, improvements in imaging in muscle invasive tumor, in imaging or in response assessment of a disease of a tumor within the bladder wall, would have an important potential impact on the management overall of muscle invasive bladder cancer, regarding various aspects of disease management. For example, improvement of response assessment and elaborating on newer therapies, given adjuvantly before cystectomy.

But most importantly, I would say identification of outlier responders, so the very good responses in particular that may be spared of any radical local treatment, including radical cystectomy and potentially also include radical immunotherapy in the near future. Of course, anticipation of relapse is another important topic, to which investing on newer tools and newer staging techniques. As a brief story of VI-RADS development since the early publication by Dr. Panabianco and colleagues in 2018. Before that, MRI was characterized in general by a suboptimal accuracy and suboptimal specificity and sensitivity to allow and to diagnose muscle invasive tumor. And VI-RADS scores being developed with the specific aim of diagnosis, of dissecting the proportion of patients with muscle invasive tumor from the non-muscle invasive tumor in treatment naive patients. So patients without any prior treatment, including surgery, including systemic therapies for their disease. The scoring has been validated perspectively by a number of additional studies by meta-analysis.

So this is an established method to diagnose a muscle invasive tumor. Of course, they're used in a different context, in particular in the response assessment post-neoadjuvant therapies. It's still experimental. It's still a matter of debate. This is actually what we aim to do within the PURE-01 study. The design of the study is pretty well known, the PURE-01 study. Three cycles of neoadjuvant Pembro in T2-4N0M0 muscle invisible bladder cancer. The patient was staged before Pembro after TURBT, it's important, with MRI. And re-stage after Pembro, just before radical cystectomy with another MRI of the pelvis. There was a lot of additional biomarker samples, as you know. So this is the reason why we introduced, in our analysis, the concept of the score and the category of VI-RADS: 0, indicating the case in which we had no evidence of residual disease post-TURBT or post-TURBT and Pembrolizumab. The endpoints were the associations between VI-RADS pre and post-Pembro and pathological response, and the association between VI-RADS scores and outcomes in particular event survival and overall survival.

In total, we identified 110 patients. That's suitable data for analysis. So accounting for a total of 220 MRI scans, the population of patient for the analysis is consistent pretty much with the con population, the ITT population of the overall PURE-01 study. It's important to note that you can see here the distribution of VI-RADS scores pre and post-Pembro. But at the end, just around the 21% of the patient had the change from 0-3 scores to 4-5, or vice versa. So actually, a response to treatment for non-muscle invasive disease to muscle invasive, or from muscle invasive to non-muscle invasive disease, was obtained in a minority of patients, just in one quarter of patients, 21% of the patients, while the rest did not reveal any major change in VI-RADS scores between pre and post scans. The associations between VI-RADS scores dichotomize as 0-3, so non muscle invasive tumor, and 4-5 together with other co-variants like clinical T-stage or biomarkers like TMB and CPS are shown here.

For the sake of time, we present just a Multi-variable analysis, including post-Pembro VI-RADS on the left and pre-Pembro VI-RADS on the right. You can see that the accuracy was pretty much high throughout the analysis. In particular, when including post-Pembro VI-RADS, we reached an area under the curve of 0.90, so a pretty high accuracy of diagnosing non-muscle invasive disease with the use of post-therapy assessment with the use of MRI. A little lower scores were obtained when looking at the pathologic complete response as the endpoint for us for the association analysis. Again here, with post-VI-RADS scores, we reached an area under the curve of 0.80. Most importantly, I will say the association between VI-RADS course and survivals are intriguing. These are the associations between post-Pembro VI-RADS and event-free survival and overall survival. You can see here that also when dichotomizing patients between 0-3 and 4-5 post-Pembro, we identified that those patients who achieve a non-muscle invasive disease start to MRI post-Pembro benefited with the long-term event-free survival at much higher numerically and statistically as compared to non-responding patients.

And the same for overall survival. We realized that the long-term... Also for the design point, there was a disconnection of the curves. So again here, a way of potentially identified in population of patients who may be spared any radical surgery on the bladder tumor after the identification of a complete or near complete response to Pembro. Weaker associations, in particular with overall survival, was seen by using pre-Pembro VI-RADS. Indicating that also in cases with the minimal disease, in which apparently we do not see any major change between pre-Pembro and post-Pembro scans, there is still a potential for benefit, at least in overall survival. Because here, we don't see in pre-Pembro VI-RADS any major disconnection in overall survival. But instead, as you remember, we have seen this disconnection with post-Pembro when analyzing the response to treatment. So this is interesting of course for additional studies.

And in terms of biomarkers, it's interesting to note that when associating the gene expression analysis in TURBT and the pre-Pembro MRI scans, we realized that there was an association between markers associated with non-response to immunotherapy and higher VI-RADS scores. A particular gene signature associated with angiogenesis, cancer associated fibroblast, EMT or myogenesis were associated and we're seen with the higher risk scores in more advanced tumors almost in higher VI-RADS scores. And conversely, lower VI-RADS scores were associated with the higher Interferon Gamma, Interferon Alpha gene signature scores that were historically, and also in this study, associated with benefit with the immunotherapy. So lower scores and lower stages, better associated, much higher association with biomarkers related to benefit with immunotherapy. Regarding DNA duration, we do not see any major association between genomic profiling, and the VI-RADS and pre-Pembro VI-RADS, with the only exception of RAF1 genomic alteration that were more represented in lower VI-RADS scores in 21.5% or lower VI-RADS pre-Pembro.

So in conclusion, MRI revealed also, and in particular with the use of VI-RADS, as a way of staging and evaluating response to neoadjuvant immune therapy, revealed the potential way of selecting patients in the near future or in the context of course with clinical studies. For which, we may envision strategies that they're aimed to spare any radical local therapy on the primary tumor and may continue with systemic therapy in case of major response or additional strategies using your drugs. So implementation of MRI, according to our practice and our judgment, is required and may be quite useful for a physician and for the patient to improve also the patient counseling after neoadjuvant therapy. Thank you so much.

Ashish Kamat: Thanks Andrea. And this really is a large body of work that you've been doing, as it comes to this particular field. So congratulations once again, not only on the work that you've done but also the breaking abstract that you had recently. A couple of questions. If you had to advise clinicians today who say, "Well all that data is great, but help me make some sense of it. How can I use the MRI, the VI-RADS system in my clinical practice today?" What would be your pearls of wisdom for them?

Andrea Necchi: Yeah. Great question. I think that if you have the evidence of VI-RADS 0-3 categories, so the evidence of non-muscle invasive disease at disease staging baseline before starting any neoadjuvant therapy, you should very deeply discuss with the patient regarding the need to provide the patient with any systemic therapy added to radical local treatment on the primary tumor, either radical cystectomy or chemo radiation treatment or therapy. But if you consider that the reassessment with MRI after any neoadjuvant therapy, in this case with immune therapy. But I assume that the same could be applied also with the standard chemotherapy or in combination of chemo-immunotherapy in the near future maybe. There is reliably the possibility of discussing with the patient the possibility of having, in some cases or in the majority cases, their bladders spared.
And building on these responses by elaborating on bladder sparing strategies. That may include of course radiation therapy, or maybe in some selected patients, observation alone after a systemic therapy or TURBT as a noninvasive way of reassessment surgically the response instead of radical cystectomy. So a different way of reanalyzing the response and re-discussing with the patient the entire strategy, which is result based and evidence based, instead of moving since the very beginning towards the end with a fixed paradigm. I think that the flexibility is the winning strategy and the MRI is well suited within this flexible strategy, that may benefit of course a lot of patients.

Ashish Kamat: Yeah. I think that's a great point that you make. That the strategy that we have currently... And obviously, overall survival and cure of the patient is important. But building in the MRI and other assessments to improve our actual staging of patients before making that final decision about local consolidation is very important. And in fact, Andrea, you're going to be a critical part of the IBCG consensus meeting, that is going to actually discuss a lot of these endpoints when it comes to bladder conservation, et cetera. So looking forward to more discussion there. Another question I wanted to ask you is, you showed some correlation between the MRI score of course, and the molecular profile of the tumors. Do you think that there's an actual correlation or you think it's just a reflection of the less aggressive tumors by virtue of size and their profiling? Some thoughts there?

Andrea Necchi: Yeah. We still do not know, as we were unable basically to evaluate the same association non-post treatment material, because of the fact that most of the cases we achieved the pathological complete response. So we do not have any viable tissue, any viable tumor available post therapy to make associations. But as a matter of fact, it seems that lower stage tumors are associated with features that may pertain a better response to immunotherapy in general. So this is not something that seems to be time dependent, but seems to be biology dependent. So less advanced disease seem to be maybe more likely to respond to immunotherapy.

This is an interesting context that may re-discuss maybe the possibility of administering immunotherapy, also in the cases in which we do not see any major or any viable disease on the [inaudible 00:14:53] disease that they have with the MRI after TURBT at baseline. So this is an important point, an important focus on the primary tumor that should be matching my view with the body of knowledge that has been developed with liquid biomarkers and liquid biopsies, in particular CTDNA, which is I would say the ideal partner with this type of analysis.

So in the near future, the availability and the possibility to combine the data with CTDNA, with regards to the systemic disease, to this data that are focused on the bladder wall, on the bladder tumor may allow us to develop composite models that may allow reliably to envision strategies of bladder sparing approaches, or systemic therapy alone, or completely different approaches that are based on the response and the monitoring of disease based on biomarkers. That may reshape entirely the way we currently discuss the treatment paradigm of muscle invasive disease, so historical. And renew the discussion regarding radical cystectomy or trimodality therapy, that are basically made at the beginning of the story, should be reassessed at the end or meanwhile while on treatment based on the response. So a response based therapy accumulating data from different biomarkers may be one of the keys for the success from both sides, from physician and from patient side.

Ashish Kamat: Absolutely. Another great point, Andrea. And lastly, I want to ask you with all the body of data that you have and the work that you've done, any thoughts about going beyond the VI-RADS system and incorporating maybe machine learning or AI into the correlation of MRI with response?

Andrea Necchi: Yeah. A deep type of analysis and huge efforts are ongoing worldwide from different centers regarding artificial intelligence. And the way of combining data from the radiological tools with the pathology samples and two more biomarker samples, so a lot of data. We also have an ongoing collaboration with the [inaudible 00:17:13] and Memorial Sloan Kettering aim to incorporate this data within a different body of data, that are precisely into develop artificial intelligence tool, as you mentioned. Specifically applied to the prediction of pathological response to any newer systemic therapy, including immunotherapy in muscle-invasive tumor. This is of course one of the next steps. Of course, the translation into real world practice is a bit different to envision at this time point, at the time being. But of course, it's another exciting path for the ongoing research.

Ashish Kamat: Great. Professor Necchi, again, thank you so much for taking the time. It was a pleasure chatting with you.

Andrea Necchi: Thank you. It's a pleasure. It's all mine. Thank you. Thank you so much.