The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the bladder cancer clinical updates you need to know from ESMO 2025.
Hi, everyone, and thank you, Doctor Sarzan. Uh, uh, we had excellent talk about the prostate cancer where we covered a lot of things, including precision oncology. Um, I have the opportunity to present on bladder cancer. Uh, and we have like amazing, exciting abstract and, uh, trials which were presented, and two of them were published in Uh, N AGM. So the three, key studies are keynote 905. This is one of my favorite, uh, that SSO presentation just because this covers the patient who are basically says ineligible MIBC and uh some unmet need in this group. The second one is I'm vigor 011. Kind of highlight how innovation and precision oncology play into role in muscle invasive bladder cancer. And finally, the Cimabvidotin and to repellumab is another, uh, frontline uh HER2 directed therapy. So first, I'll go through the perioerative info vidotin plus pembrorozumab, which is a phase 3 keynote 905 study. Um, uh, and this study was many years of hard work from the authors where we know that in MIBC 50% of patients are and eligible or they are not good candidate for surgery or like any treatment just because of the comorbidities. Historically, we are struggling to find a treatment for those patients and, uh, and, and we don't have any good trials to suggest that and keynote 905 kind of demons. Studied some key findings. Uh, just to walk through some key eligibility criteria or study designs, uh, study included T2 T4A or T1 to T4A N1, uh clinical stage and uh include a patient with good than 50% ureter histology and uh patient were sys and eligible based on the Galski criteria or some patients declined uh uh the chemotherapy. And uh uh at the interim analysis, uh patient uh were uh in the uh intervention arm receive info to map the rotine 1.25 mg per kg, uh 3 weekly for three cycles, and pembrozumab 200 mg Q3 weekly for 3 cycles. And uh patient underwent radical cystectomy plus pelvic lymph node dissection. Um, and followed by adjuvant, uh, EV for 3 weekly for 6 cycles and perzumab for 14 cycles. In observation arm, which was randomized 1 to 1, uh, they received, uh, RC plus RP PLND and on observation after surgery. The primary endpoint event free survival and secondary endpoint include overall survival and pathological complete response. So these are the, this is the baseline characteristics, uh, which is, which is equally distributed between EV group versus control group. Uh, interestingly, greater than 75% were the major part of the patient population, uh, in EV Pembroke group, and also this trial included ECOG of 2, which is generally considered poor, and most of the trials don't enroll patients with ECOG of 2. And uh uh significant number of the patients in both arm uh were ineligible and as we can see in the clinical stage group as well, T3, T4A, where the majority of the patients in both groups. And uh most, uh, most of the uh histology in both groups were pure urethelial, which were 89 and 92% in the control arm. And uh to come to the result, we see the massive improvement in the event free survival with hazard ratio of 0.40, which is quite significant and historically, we haven't seen this kind of Uh, outcome in, uh, non-muscle invasive bladder cancer. And this is the first phase three trial to show the significant EFS improvement and, uh, uh, with significant P value. And as we can note that uh uh 16.7% of the patient in the control arm receive adjuvant nivolumab at the time of the cutoff. And we can see uh different uh EFF benefit across all subgroups including different ages, uh, functional status, and also irrespective of the PDL one status. And this trial also found significant improvement in overall survival with median uh overall survival of 41.7 month in control arm, and it did not reach in, uh, in the EV Pembro arm. Hazard ratio was 0.50 and P value of 0.002. And it's also important to note that 4.7% in the EV Pembro arm and 26% in the control arm received subsequent therapy for the recurrent of metastatic disease. And we can see uh the benefit and overall survival across all subgroups in EV Pembro arm. Looking at the pathological CR rate, which is defined as absence of the viral tissue in the examined tissue from the radical cystectomy and pelvic lymphal dissection. Uh, there was like 57% pathological response rate in the EV pemb arm compared to the control arm, which is very significant and historically, if we look at the PAT CR in any trial, this is one of the highest that we have seen. And the trial uh did not include any patient who refused, who did not undergo surgery, uh, including those who achieved the complete response in the radiological findings, and they were considered non-responders. And when uh uh uh stratified by the PAT CR versus no PAT CR, we can see that those who obtained the PAT CR in the EV Pembro arm had significant uh uh improvement in, in the event free survival as compared to. not, but it's uh still in the those who didn't achieve the PAT CR in both EV and Pembro arm, we can see that there's a median overall survival of 26 months in EV Pembro arm and 14 months in control arm hazard ratio of 0.76, but confident interval was not significant. And adverse event was, uh, that what we know about the most of the 3 adverse event, uh, were mainly in the EV Pembro, which we knew about and uh death related to uh the treatment was uh 7.8% in EV Pembro arm and 5.7% in the control arm. Most common treatment emergen adverse effects, uh, the incidence greater than 15% in all phases of the analysis. And uh during surgery phase, the incidents were greater than 3%. So key take away from the keynote 905. This is the first phase 3 trial to show uh significant improvement in clinical outcomes in this uh subset of the patient population, which is C and eligible, uh, and, uh, this is significant improvement uh in the, uh, there's significant improvement in the event survival, overall survival, and the PAT CR rate. Safety profile remain manageable and consistent with the prior studies. So, bottom line from this study is that this uh opens a gateway for our patients who are uh not good candidate for periooperative uh chemotherapy. Moving to the invigor 011 phase which is uh phase three trial uh of circulating tumor DNA guided adjuvant Atizo versus placebo in the muscle invasive bladder cancer. Uh, as we know that 50% of the patient, uh, have recurrence of the cancer after surgery. So this trial is many, uh, uh, kind of, uh, many years of hard work from the authors and also innovation and precision oncology. Uh, how we can utilize the CTDNA as well as making a decision for the treatment. Uh, as we know, IV 010 did not show any benefit of adjuvant, um, alizumab, uh, in no unselected group of MIBC. But here author what smartly they did was they, uh, pick up the patient uh who has like a uh PT24A and then PT0T4A um uh uh. sample and they uh monitor CTDNA 6 weekly and also uh radiological monitoring every 12 weekly. Those patients who were positive for CTTN anytime during serial monitoring were randomized in 2 to 1 fashion to etizo versus placebo, and those patients who were negative were not given any treatment and monitored all along. These are the patient characteristic uh between the etizo and the placebo arm. As we can see, it's kind of similar between two. the tumor stage, uh, post cystectomy uh was T3, T4, uh, in 70, more than 70% in both the placebo and etizo. Even, uh, CTDNA were positive, around 60% in uh both placebo and etizolam, and subsequent tests were positive in 40% or 41% in placebo and the etizolam. So looking at the primary endpoint with DC DFS, those patients who tested positive for the CTDNA showed significant improvement in disease-free survival with Etizo with median um uh DFS of 9.9 months versus 4.8 months with a placebo, with a P value of 0.0047. Overall survival, we, we can see that there's a significant difference in overall survival in a patient who had CDDNA positive and receive Etizolizumab. Uh overall survival of median of 32.8 months versus 21.1 month in the placebo arm, uh, with a P value of 0.0131. And we can see the PFS and the DFS uh DFS and the overall survival benefit across all the subgroup, um, including the pathological stage and PD PDL one status. And CTDNA clearance and concentration, uh, CTDNA clearance was much better in ETZ arm as compared to the placebo. So there was a difference of about 10.7. And we can see that at cycle 3 and cycle 45, there was CTDNA concentration kind of cleared in uh in the Etizo arm. One of the interesting part of this study is how to stratify patients who are CDDNA negative because this kind of truly highlights who are the patients who need the treatment because we might be giving unnecessary treatment to the patient. And this study showed that those patients who are CTTA negative tend to have very good prognosis with better overall survival with 888.4% TFS at 2 years' time point and overall survival of 97.1 97.1% at 2 years' time point. And safety wise, uh, there's no new signal, uh the uh the side effects are similar to what we know previously. And the key takeaways from the ambiguous user one is that tumor involved CTDNA guided adjuvant significantly improve the DFS and overall survival, and the CTDNA negative patient, uh, continue to have good prognosis overall, and this support the de-escalation treatment for this group of the patient. And CTDNA enhance the risk determination beyond pathological staging. So this could also have like CDDNA uh rule of CDDNA in the advanced urial cause cancer as well. So moving on, uh, and, uh, and to further uh solve this problem, so we have modern trial going on where our own doctor Stephanie Berg is uh in this trial where they are randomizing a patient based on the CTDNA positive or CTDNA negative. So moving on to like metastatic urethral carcinoma, now this is the era of the precision oncology where we are seeing uh an antibody drug conjugate which is revolinizing the treatment of the bladder cancer and other cancer as well. We have a infoumab vedotin and tratuzumab diroicine which have different target nectin 4 for EV and HER24 transzumab droicine. Uh, theitumab vegetine target the HER2 and with the MMA payload and uh. Moving on to the next trial, which is ditumabiddotin plus toriliumab. Uh, this is a phase 3 RC4AC016 study. Uh, this was conducted in China, and, uh, this is a study design. This included locally advanced for metastatic, uh, urethelial carcinoma with confirmed HER2 expression with IHC1+ 2+ or 3+, and patients were eligible for cisplatin or carboplatin. And study randomized uh 1 to 1 to decitoma vidotin plus toriella and uh to gem cytine cisplatin carboplatin. Uh, and dual primary endpoint for the study was PFS and overall survival and secondary endpoints were PFS or DSR duration of response. This is baseline characteristic with DV + T versus chemo, uh, overall similar between two groups, but we can see that interestingly the upper tract was significantly higher rolled in this group, 45% in DVT arm plus 50% in the chemo arm. Uh, additionally, we can, we noticed that IHC 2+ or 3+ from the majority of the patient, but uh there were one quarter of the patient in both TB plus T and chemo arm with IHC+. This is important clinically because HER2 is, we have approved drug for the HER2 and this with a different, this trial with a different payload targeting HER2 and uh combination of immunotherapy gives a significant outcome in the patients. And uh trial met the primary endpoint with significant improvements progression free survival with median PFS of 31, 13.1 month versus 6.5 months with the chemo, uh, hazard ratio of 0.36. So there's a significant risk of reduction of death by almost 64% of DB + T. This is a good Kaplan-meyer curve we can see and good separation of curve early on during the treatment. And PFS was uh uh better across all the subgroups including HER21+ and HER2 2 + 3+ by IHC and there improvement were seen across like all PDL one expression as well. In terms of overall survival, this trial found a significant improvement in overall survival with median OS of 31.5 month in DV + D versus 16.9 in chemo with hazard ratio of 0.54%. This is like significant improvement in overall survival, which is we don't generally do the cost trial comparison, but similar to EB plus Pembro. In subgroup analysis, uh, overall survival was benefited across all specified subgroup, including ISC2 + 3+ and IC 1+, uh including both upper and the lower urinary tract, uh, carcinoma. So, with regards to the tumor response, there was significant tumor response to DV + T with 76.1% versus 50.2% in the chemo arm. Additionally, the duration of response was quite long for the EB+ Pembro. At 18 months time point, 42% patient had uh continued response as compared to 8.7 months in the chemo arm. And safety wise, uh, it's, it's, there were 55% of the patient had grade 3 treatment-related emergent, uh, side effects in DB + T compared to 86.9% of the chemo arm. The chemo arm mostly had hematological toxicities, but DV and plus T arm had mostly neuropathy and other toxicities. So, and toxicities was pretty manageable in the DB plus TR. So key takeaways from this trial. DB + D significantly improved overall survival compared to the chemo, and there was significant improvement overall response rate, duration of response as compared to the chemotherapy. More importantly, the drug combination was effective across all HER2 expression and safety profile seems to be favorable compared to the chemo. So the next question comes is that is efficay similar in ERBB2 mutated urothelial carcinoma or is this because this trial was only done in China, so it has to be generalizable to other patient population as well. Uh, moving on to like what ADC trial we have, uh, our own doctor, uh, McGregor is currently running phase 12 trial with the dual, uh, ADCs with infertumabvidotium and saczumabviti again as a frontline treatment. Uh, so the result is highly weighted for this trial as well. Now, I'll uh hand over to Doctor McGregor to give his expert comment on this, on those trials. Yeah, I mean, great discussion. Um, I think that, um, but I, I would say that we probably had the most um practice changing data in bladder to come out of, um, ESO. I think as you alluded to, I think the keynote 905 is really the first of what's to come, um, that I think would be curing a lot more patients in the perioperative, um, setting. Um, so I think, you know, patients right now who cannot get cisplatin, the standing here. I think that the The vanization was, um, it has a lot of equipoise without a doubt. Um, and I think the results are quite impressive with the near over 60% path response path CR rate if you look at pages that actually went to um surgery and promote survival, DFS. I do think there's a lot more questions than answers as you think about how to best use this data in the clinic. You know, as you allude to, this is a, a sandwich approach where patients got EV for time 3 seconds of 4, and then, you know, they. Additional, um, 6 EV Pembro afterwards, follows Pembro. How much of that do we really need? Um, I think there's a lot of discussion that's ongoing. I think right now we're left with the data. Um, and, you know, that is the approach they use. A third of patients didn't get maintenance EV. Why was that? What was the issues that happened there? So I think there's gonna be a lot more data to come out of it, but I think it really, really It is an exciting option for our patients. And to be honest, I think the majority of the patients on that trial are qualified for EV Pembro for the current indication right now. Um, T3, T4, and 1, that's locally advanced disease you get EV Pembro. And so I think this is probably practice changing today if you have a patient with locally advanced, um, disease that's borderline resectable, I think EV Pembrose certainly is appealing. I hope there'll be a label change in the um very, very near future. I look forward to the data in eligible patients. Um I think we're all hoping for even higher reject response rates, just giving those patients that can be healthier and plus they're gonna be giving 4 cycles um of EVE prior to surgery instead of just 3. Um, and to your point in the future, I think, yes, there is gonna be probably a case we're gonna be looking towards um a A world in which we're doing latter sparing, right, where we're going to be doing EDP alone with the past past CR of 60% higher. I think that's not outside of our possibility, um, but I do think now we're gonna do what do we do post CDP, right? So this is amazing for the patient to do what we do post CVP I think trials are ongoing. They're going to answer that question um going forward. I think we have the data um DXD plus platinum platinum Gem, um, that's gonna be opening soon. Um, there's certainly a role for HR2 ADCs, um, so I think a lot more to come. Uh, I think that the Invigo data, I was a little bit less impressed than maybe you were. I mean, I think. That it's, it's compelling data. It's a proof of concept. I think to me what it shows we saw a similar data for just one time point from checkpoint 274, and I think one time point just isn't enough. So I think the idea that we would withhold ad data based on a single negative time point is not the right answer. And so I do think moderates incredibly incredibly important. I think that, you know, yeah, if you're negative, you stay negative, you do great. Well, that, that sort of makes sense, right? If your scans are negative, you stay negative, you do great as well. So I think that that, that, that, that arm is good, but even then, some patients relapse on scans with a negative DNA. So I think it's certainly not a um perfect, perfect biomarker. I think maybe it's a little bit um to Late as we um like now that we have EDP moving in how we, how are we going to be using this um in the um in the In the EVP era and everything, I think it's unknown. I personally still think modern is incredibly important, um, and so I would strongly encourage anyone who has patience in that space. So, um, T2 or greater. Post neo adjuvant therapy, um, who have a positive Nevarela versus Nevo negative upfront Neva versus serial moderating Nevo at time of conversion. So slightly different what we did at Teso, right? In Teso, if they were negative, they just watched them and they only got a Tesla positive. So I think. It would be an important question. Um, and then I think HER2 ADCs are here to stay, as I allude to TDXCs are approved in the United States as an option for patients who are IC 3+, um, post lines of therapy, so I think it's a great option. I think the uh DVT data really is proof that, you know, again, as we saw. Phase one, phase two trials that this combination is very active and tolerable and supports the phase 3 trial that's going to the US. What I will point out is that that that trial allowed her to 1 +. Um, so I think that, that, that does separate it from where we are right now. And so this idea that even 1 + this bystander effect could be um beneficial. Yeah, no, just one thing before because we need to get a kidney. The, the only, the two things is this data was the drug is not available to my knowledge in the US. One plus, but there's a trial ongoing of Pembro versus platinum, right? And the HER2, I think HR 1+ is the majority of patients, but I think what, what's going to happen, people are going to get EV Pembro. They're gonna stay in HER2. It's gonna be 1. Or more in the United States and people are going to give a single agent with or without PD1 of the settlement blight. I think that's a possibility. The second thing about CTDNA, Tom's study is very smart, knowing that we need to be just set the record straight. It was designed with Joachim Belmont. OK. Joachim is the co-senior author on the New England Journal of Medicine paper, and it's very Smart. It's not one CTDNA negative you don't do and one positive. When you go at what Tom presented in the past, if you have one negative and you follow them, 35% of patients will recur. It was a very smart test. You continue, continue, continue, and once it's positive, you randomize or in the beginning. And even with that, if you continue to be negative, 12% of patients. Um, you know, will, uh, will recur with negative CTDNA. The problem I see in this, uh, thing is, one is atizo the right to drug. OK, I know it's done. And second, what if you have an eligibility criteria after cystectomy that meet, you know, nivolumab checkmate 274, what are you gonna do with the negative CTDNA? What would you do? Would you give them? Well, I think that's the key question, right? I think serial, I think it really highlights that a single time point is not enough. Like CTA is a dynamic biomark you need to follow it and withholding adjectator based on one point is not good. I think to your point, Tony, that's where modern is important. Modern is. Looking at patients who are negative, upfront Nivvo or modern and Nivvo at time and converted if they're negative. And I think that that's asking an important question that this trial actually supports, right? This trial so the patients that are positive do get benefit. Last question, sorry, Mike. 8 weeks after cystectomy, patient comes to see you doing great. They want adjuvannivolumab, let's say they're T4 N+. You do CT DNA on them, red, it's negative. It came back. Are you going to give adjuvannivo? I put my modern. Oh my God, this is the modern. This is the way my hope is this will not happen anymore because EV Pembro is going to change the field and we're not going to be seeing those type of responses post neoadjuvant. You should run for office. You dodged my question in a row. Congratulations. OK, I'm done. Um, no, but I think it's exciting time for data. I think there was a lot of data, um, looking, I think BCG plus PD1, um, exciting that what does that mean? I think there's a lot of problems with the end points there, so I don't think we'll be using a whole lot. I mean other novel ADCs, there's the data DXD plus a digit PA1 with I guess closest 70% response rate in s ineligible patients. So I think um novel approaches um will certainly be coming, coming up. I, I agree with you CTA is Certainly here to stay, and I think this data gives screens that will probably be looking to incorporate that into the EV Pembro. Ea um as we move uh forward. Fantastic. Well, again, thank you, Doctor Tapa, Doctor McGregor, Doctor Shaweri for very robust discussion on bladder cancer.
