Chapters Transcript Video Peri-operative Muscle-Invasive Bladder Cancer (MIBC) Management Back to Symposium I'd like to hop right in and discuss some of the management that we have for a perioperative muscle invasive bladder cancer and as Ferna mentioned, this presentation changed quite a bit over the course of the past week. So I'd like to jump right in and discuss what we have discussed going forward. I just mentioned a few personal disclosures, uh, uh, career development award, uh, the Medical College of Virginia and Bristol My qui and institutional, but otherwise too relevant. And looking at the overview for this presentation I'd like to look at a little bit of historical background and how that contributed to the development of a number of adjuvant regimens for muscle invasive bladder cancer. ultimately the sandwich approach and peroperative, both neoadjuvant and adjuvant therapy for muscle invasive bladder cancer, uh, a discussion in terms on the bladder spearing approach, and then some thoughts that we have based on some of this new data, something that is very much in flux. Quite early we recognized that just a cystectomy alone for patients with muscle invasive bladder cancer was often not sufficient. There were a significant number of patients that were still having recurrence despite what we hoped would be curative therapy and even decades ago recognized the role of cisplatin in platinum-based chemotherapy. regiments and the setting and I highlight one of the earlier studies from Grossman etal from 2003, sort of highlighting that and even more recently we had additional studies such as the Gtouge Vesper study which more or less suggested that docent's and that in um would be superior from uh Jimiss. And the neoadjuvant setting. Now the study did not show a no benefit when all patients, which included both the neoadjuvant and adjuvant studies, and yes there were some caveats in terms of this individual study such as the number of cycles, etc. but still just highlighting the role that cisplatin-based chemotherapy had up until just a relatively short time ago and has been seen in a number of other studies such as the Coxton study as well. However, even with that information, we realized that there's still too many patients that were having recurrences even in the setting of such intensive chemotherapy, and that launched the search for additional adjuvant regimens and taking the lead in that particular perspective were a number of immunotherapies which were being brought earlier uh early from the metastatic setting that could be used. The first study highlighting and one of the first with the positive we saw was the uh Checkmate 274 study which was one year of admin volumab in uh comparison to placebo and it had both an EFS, and OS benefit at multiple time points and to become standard of care. On the same lines, there is the ambassador study that was actually led by my mentor at the NIH, Doctor Andrea Pallo, and, uh, somewhat similar study with asthma and permelisma for one year, uh, notably in comparison with observation. This study also demonstrated, uh, DFS benefit. Now those uh data from this study is still maturing. However, it's worthy to note that once the adjuvant neoed data became available after 90+% accrual, a number of patients withdrew consent from this study and went to get their adjuvant pneumolimab. So even though that OS data is maturing, it's possible that we might not see any benefit at that point. So that's at least the caveat that we have for this particular agent. Now even in this setting we had a 3rd study to make things more complicated that actually had resulted earlier than, uh, the PER study, and that was adjuman atizilluzumab and interestingly that had no DFS benefit. Now the researchers from this study dug a little bit deeper to look at the study, especially in light of the other positive studies, and rice, when we started separating things by a patient's CTDNA status, we had some very interesting results. As expected, patients that had CTD uh CTDNA negative, suggesting less residual disease, fared better than those with CTDNA positivity, but in that CTDNA positive patients, they did in fact seem to benefit from atiliumab, and from that Invigor, uh O1O study developed the, uh, CT guided Adin Atiliab study Invigor 011. And in this study, a similar population of patients with those high risk features after neoadjuvant therapy or with no therapy and refused additional adjuvant after cystectomy, they're, uh, serially assessed for their CTDNA status, and only those patients that were CTDNA positive were randomized to artillizumab or a placebo. And in that setting and with data that was just presented, there is both a DFS and OS benefit in that setting, suggesting a possible role for using the CTDNA guided approach to better gauge who is the optimal candidate for this type of therapy. Now at the same time, this idea of CTDNA used for guiding therapy is already in play in other clinical trials such as a modern study which is ongoing. In this study, patients that are CTDNA positive we get randomized to either novolimab, which we agree the standard of care in the setting, or having an escalation of care for an additional agent, uh, to try to improve the outcomes in the setting. Well, those that were CTDNA negative would be random. As to either that volment or or to be randomized to a CTDNA uh guided approach and only to start immunotherapy once they turn positive and again as I mentioned before, that study is ongoing but still highlighting the role that, uh, could guide how adjuvant therapy is used in this particular place. Now even with that neoadjuvant and advent data, I think some of the, um, even more exciting data is coming in the perioperative setting with both neoadjuvant and adjuvant regiments. Uh, a couple of months ago we had the results that emerged from the Niagara study which looked at the addition of durbaumab toysis in the neoadjugen setting but then continuing durbaumab in the adjuvant setting for an additional 8 cycles of therapy. In this setting we had an improvement of approximately 10% total of pathological complete responses as well as uh EFS benefit and bringing that into a standard of care, uh, in the setting. You know, interestingly, one of the most exciting studies that resulted in this, uh, most recent ASCO was a Keynote 905 study, also known as EV 303. This study compared no adjunct therapy in patients that were cisplatin ineligible to observation in the adjuvant setting to a sandwich approach with enforced me and dotin plus pembrolizumab in the neoadjuvant setting, cystectomy and lymph node dissection, additional EV pembro in the adjuvant setting, and then continuing for approximately 8 additional cycles of pembro monotherapy after that. In the study we had 170 patients that are randomized to both arms with approximately 150 patients ultimately undergoing therapy in both sides and, uh, notably there was, um, a quite striking EFS as well as OS benefit, so it's a potential role, uh, for this new therapy that we'll uh discuss in more details. And another very exciting aspect was the fact that in this population that was treated with a. we had close to 60% pathological responses compared to just under 9% for the control population which actually had not undergone any other type of neuroact therapy other than the TRBT that might have been done in terms of diagnosis. Who setting we'll still be grappling with this in terms of, uh, what's going for the future and I'll circle back around to this at the end of the presentation. Now it would be remiss to discuss all these options in terms of the national approach without also highlighting some of the bladder sparing approaches that we talked about and bettering Doctor Carrere's talk, uh, the interesting perspective. Really briefly, as we're talking about tri-modality therapy, which has always remained an option for patients in terms of the muscle base of bladder cancer, this is consisting of maximal TURBT paired with whole bladder radiation as well as some form of chemo sensitizing radiation, most commonly low dose cisplatin, 5humidomycin C, uh, or genccitabine, often with additional boost doses of radiation to the site of, uh, the tumor. And in some cases radiation to high risk lymph nodes uh based on the discretion of the treating team. And given this role, our colleagues here at the Fox Chase had actually, um, put forward a number of groundbreaking, uh, clinical trials in this particular space, namely the retain 1 and 2 clinical trials actually performed by some folks that are here today. And the study for a retain one, this was 3 cycles of doses in fact with TURBT before starting therapy, TURBT at the end of treatment. And from the original specimen, looking for a particular mutations that have been previously from the literature, been shown to suggest a higher sensitivity to plain-based chemotherapy. Patients that had um the presence of these mutations as well as uh negative responses were allocated to active surveillance. Again this is not a randomized study, whereas those that still had residual disease at the time of this, um, at the end of this treatment were allocated to various forms of treatment depending on the pathology that was seen, uh, in this study. As part of this, we had a total of 70 patients that were ultimately in the intention to treat arm and 25 that were mutation positive and with no residual disease that were therefore per protocol allocated to the active surveillance. The few others instantly that were also, uh, moved forward with the active surveillance as well. Uh, but notably in terms of the main endpoint, which is 2 year metastasis for survival, it was over 70%, uh, in terms of the response for, uh, this particular modality. However, there were patients that still did have death due to, uh, bladder cancer, so something that's still ongoing. Based on the results of this, we, uh, worked on the next iteration of the retained trial, the retain 2, very similar in terms of overall structure, but notably we have the addition of nivolumab to dosin and VAC for those three cycles and we removed one of those genes. So we just had ATM RB1 and ERCC2 as the sensitizing mutations that we want to focus on, but a similar allocation in terms of whether patients would move forward with after surveillance or go to some form of treatment up front. In this, um, uh, earlier preliminary data we had the 70 patients intend to treat AM, uh, 23 originally signed, but ultimately 22 went after surveillance and in our preliminary data close to 8% without metastasis, and this was still ongoing and actually colleague, uh, Dohatali will be presenting updated data on this in just a few months in terms of this clinical trial and its results and still thinking about the future. So think about all these options and taking a little bit of a step back. I like to think of where we are in terms of what I call the current treatment, but I'd have to take the big caveat that this is just pre-ASO, the dark ages of about last week. So in the patients that would be CISP plan eligible, we still had doseins in VAC. In terms of GC would probably actually favor the neoadjuvant, uh, and aspirin combination for the Niagara study, which is gymyserva with adjuterval that as well. In terms of the abdomen setting, for patients that didn't have new adjuvant therapy for any reason, such as upstaging at the time of surgery. Cisplatin-based chemotherapy is still a, uh, guideline based recommendation with either dose and send back or gymsy, and we also have the nivolumab and pembroliab that I mentioned before as our adjuvant options and then those that are not surgical candidates either try modality therapy or just simply definitive radiation for those that are not even fit for that modality. However, with this involving landscape, we now have the perspective of the Atizillizumab in the CT guided fashion and where that will stack up in terms of the actual use relative to pembrolizumab and volumab there are gonna be used without this, but how we continue to use CTDNA. And then also the new data that we have from the uh Keno 905 EV 303 study. Now even as I mentioned how much this has evolved over the course of the last couple days, we have to realize that there's still a lot of data that's being generated in this space right now. We have numerous studies that are ongoing and this is plan eligible as well as. Ineligible space such as the keynote B15 EV3L4 study which is the neoadjuvant EV and uh combination asin EV and impairment combination but in cisplatin eligible patients in comparison to gymsy again now in perspective we could argue whether or not that's the true standard of care number one. And also just highlighting that in the EV 303 there are patients that had refused the sine, not that they are actually ineligible. What that means in terms of our recommendations. They have the additional keynote study with Pembrogysis, Nevaysis, and Energize, as well as the Niagara 2 study, which is actually dose stents in that plus your valumab in that perioperative sandwich of neoadin and adjumin therapy as well. To round off the list, we have the Volga study and is ineligible patients which is EV plus Derva or EV erva Treme in the auction and then immunotherapy in the Erin setting that's also running as well. And again, to highlight the work that our colleagues, uh, within our group are actively involved in, we have one of the bladder sparing studies with EV Pembro with 3 cycles and actually, uh, to, uh, determine based on whether patients have ACR or not to undergo or not undergo cystectomy as well as our additional study of EV Pembroro plus the bespoke, um, um, the cancer neo uh neo antigen vaccine. So as we take a step back, we've had a lot of change that's been going on. Rocky sees a lot of things have been going and so as we take a step back and we have a lot of our discussions here, I think we go back to two of our central principles, some of the things that Doctoria highlighted that we're aiming for both the optimal oncologic outcomes as well as the optimal quality of life and really think about what that means as we're thinking about the outcomes, yes, we certainly want to make sure that people are not succumbing to their disease. They're not having metastasis and what that means in terms of local control of their disease, but it means in terms of the quality of life and who needs which treatments and how much we can think of this not just in the adjuvant setting and CTDNA, but other biomarks might be relevant who needs an escalation of treatment for a very aggressive disease, who may or may not actually need to have their prostate uh their their bladder removed. And again thinking about the quality of life data maybe that actually is not the worst outcome as we're really thinking about the options that we have available. But ultimately to try to get the best treatments, the right amounts and also thinking about how this informs how we think about the next lines of treatment, how we think about the next biomarkers, how we think about the molecular biology of the disease that might also be important determines of who might respond to those treatments that we're talking about no matter what modality that is engaged. So with that and as we lead into the discussion, I'd like to thank you very much for your time. And I certainly like to acknowledge the other members and faculty members of our group as well as the advanced practice providers and research teams that make all these things possible. urology ra on colleagues, uh, to colleagues, colleagues here, industry partners, and certainly the patients that have entrusted us with their care and in particular a special note for those interested us in the setting of clinical trials as well now and in the future. Thank you very much. Created by Related Presenters Andre Kydd, MD, PhD Assistant Professor, Department of Hematology/Oncology, Division of Genitourinary Medical Oncology
