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 GU ASCO 2025.
Without further ado, we'll move on to bladder cancer. Um, for those of you just joining, this is our ASCO 2025 conference highlights, um, with a focus on bladder cancer. I'll be joined by Doctor Bradley McGregor as our discussant for our abstracts this evening. Um, I thought there were three themes, um, that we saw in bladder cancer at ASCO. Um, first, evidence of things not seen and, and an analysis of CTDNA on the Niagara study. Um, second, the informumabvodoin plus Pembro continues to raise the bar and first sign of metastatic urothelial cancer. This was an analysis of of patients who had response to therapy and what the durability of that response was. And lastly, we will come to the comeback kid, um, of Satitus Map Gova Tan, which obviously had, um, it's FDA, um, uh, accelerated approval withdrawn. Um, we had saw some evidence of anti-tumor activity in combination with the Valluab at ASCO 2025. So, um, first again, many in this audience will be familiar with the Niagara study. This was a randomized phase 3 trial for patients with um cisplatin eligible muscle invasive bladder cancer randomized to perioperative durvalumab, so durvalumab plus gem cyst prior to cystectomy followed by Adjuvant alumab x 8 cycles or gem cyst followed by radical cystectomy and no adjuvant therapy. What this analysis looked at was CT DNA at 3 time points. So at cycle one day one of neoadjuvant therapy, just prior to radical cystectomy and then just after radical cystectomy prior to the initiation of adjuvant therapy. And, and again, as we all know that Niagara, um, the perioperative durvalumab did improve event-free survival and overall survival relative to, um, to chemotherapy alone and is FDA approved and I would say is a standard of care for the treatment of muscle invasive bladder cancer. Um, When we looked at the general population, we saw 57% of patients at baseline had CTDNA positive. At pre-radical cystectomy, that number goes down to 22%, and after cystectomy patients at 9% of patients were CTDNA positive. When we look by treatment arm, we see patients on Valumab, there was a 39% decrease from 58 to 19% in CTDNA positivity, whereas that number is a little bit lower in the comparator arm with chemotherapy at 5 29%. Um, after cystectomy again similar rates of CTDNA positivity at 8 to 10% in either treatment arm. And what we saw was that when measured at baselines, if patients were CTDNA positive, um, that was prognostic for event-free survival. So those patients who are CTDNA positive had an increased likelihood of recurrence of disease relative to those who are CTDNA negative. And then when we look at the treatment effect, we see on the top, patients who are CTDNA negative seem to have a greater benefit from perioperative to valueab with a hazard ratio of 0.45. And then we look at the bottom two curves, we see patients who are CTDNA positive seem to have benefit with their valuab, however, that hazard ratio is lower at 0.73. Again, we looked at baseline, now we'll look at um what was the clearance rate between baseline and pre-radical cystectomy. So patients treated with durvalumab had a 70% CTDNA clearance relative to the comparator arm of only 57%. And those patients who were CTDNA positive prior to cystectomy again had a worse event-free survival than those patients who were positive and then turned negative or who had CTDNA clearance and that had a hazard ratio of 0.32. Um, when we looked at the association between CT DNA status and pathologic CR on the left hand side you see patients who are CTDNA negative, about half patients had a PAT CR, half patients had a non-PathT CR, whereas on the right-hand side, patients who were CTDNA positive just prior to cystectomy, only 3% of patients had a PAT CR 97% of patients had a non-PathT CR. So again, CTDNA positivity associated with um a non-path. CR and again, in the post cystectomy, although these numbers go down drastically, those patients who are CTDNA after cystectomy prior to adjuvant therapy had a much, uh much higher risk of disease recurrence than those patients who are CTDNA DNA negative post cystectomy. And again, that has ratio is very, very small, 0.09, um, but again, that's because the um CTDNA rate after um cystectomy was so low. Um, when we look at the association between these two things, um, we see that on the top, patients who are CTDNA negative and have a PAT CR, those patients tend to do best. Then patients with CTDNA negative with a non-PAT CR, and again, patients who are CTDNA positive after cystectomy, um, did poorly regardless of whether or not they had a pathologic CR. So what are some some takeaways? Um, again, I think CTDNA is, um, powerfully prognostic. Um, if you're positive at the beginning, it's prognostic. Um, if patients were able to clear their CTDNA, um, that occurred at a higher rate in the Duvalumab arm, just prior to cystectomy, if patients were CTDNA positive, they had a low chance of accomplishing ACR and again, those patients who are CTDNA positive after cystectomy, um, That was really a poor prognostic indicator for recurrence of disease. And so I think, you know, this, um, gets us a little bit closer to perhaps being able to use this in the clinic to make clinical decisions, um, based on, um, the, um, based on the prognostic indicator of CTDNA. Um, this, uh, concept is, is actively being investigated in the modern study. This is a study for patients with muscle invasive bladder cancer, um, who have either received prior neoadjuvant chemotherapy and have persistent T2 disease or have not received prior neoadjuvant therapy and have T3 or higher disease. Patients are randomized based on CTDNA status, so if they're CTDNA positive on the top, they either get Standard of care and Ebolaab adjuvant therapy or Nevo plusrela, uh, which is a LAG3 inhibitor for patients who are CTDNA negative after cystectomy. They either get standard of care and Ebolaab or surveillance, and if they, um, CTNA becomes. Positive, then they receive no bone that therapy. So it's trying to investigate both questions at the same time, intensification of therapy for patients who are CTDNA positive and also potentially deintensification of therapy for patients who are CTDNA negative after radical cystectomy. Um. So, next we'll move on to um the first line metastatic setting, um, and this is an analysis of EV 302. Again, as many on this call are familiar, EV 302 is the large randomized phase 3 trial for patients with muscle and metastatic. Um, urothelial cancer randomized to EV Pembro or chemotherapy. Um, we know that this study is positive for, um, improvements in, um, in PFS and overall survival, and we know that patients treated with EV Pembro had a higher CR rate at 30% relative to chemotherapy at 14.5%. And we also saw, and when we looked at the ITT population versus the EV Pembro responders, we saw very similar rates of upper versus lower tract disease, visceral metastasis versus lymph node disease, um, cisplatin eligible versus cisplatin eligible, so there were no clinical factors that could help us predict which patients may be long term responses. EB Pembro. Um, but for patients who did have a response, again that 2/3 of patients who did have a response to EV Pembro, we saw that the durability of that response was about 50% at 2 years or a median duration response of 23.3 months versus chemotherapy at 7.0 months. When we look at OS among patients who had a response to therapy, 3 out of 4 or 75% of patients were alive at that 2-year mark. And when we look at overall survival among patients, and the 30% of patients who had a complete response to EB Pembro, we see 95% of those patients are alive at 2 years. So again, patients who have a a complete response to EB Pembro tend to do well long term. Um, with patients being on therapy for longer, we did not see an increase in, um, in toxicities. Um, however, we did see an increase in dose reductions of EV. We know from data that we talked about at uh GUSCO 2025 that dose reductions, um, with EV and Pembro are actually encouraged and, um, allow patients to either stay on therapy for longer and continue to get benefit or avoid chronic toxicities of therapy. Um. So again, I, I really saw this as EV Pembro raising the bar. So not only did we see higher responses relative to chemotherapy, but those patients who did achieve a response, whether it was a partial response or a complete response, um, they tended to have long durability of that response. And so, Um, I think this is another scenario where we think about, you know, we've got a very effective first line regimen. Are there ways to potentially de-escalate therapy for patients who are having prolonged benefit, especially those patients who have a a complete response to therapy. Um, the next track we'll discuss is, is also in the first time metastatic urothelial, um, setting. This is a, um, a novel nectin4 antibody drug conjugate, which was combined with Torapalaab. This is a study that was done out of China and, um, really looked at a very small number of patients, just, uh, 42 patients in this, um, to show, um, efficacy of this novel nectin 4 antibody with, uh, PD1. Again, there were 47 efficacy of valuable patients. Of them, 40 were treatment naive. Um, we see our typical kind of metastatic bladder cancer baseline characteristics on the right hand side, and what we saw in those 40 patients, um, who were evaluated was um a response rate of 88%, um, a response rate of 80%, a disease control rate of 92%, um, so very impressive anti-tumor benefits seen in this population. Um, I will note that the median follow-up was just 10.8 months, so a very early look at a small number of patients, but, um, this combination looked like it had a, uh, uh, median PFS of 12.5 months. Um, and I think what differentiates this combination from potentially EV Pembro was relatively lower rates of rash, um, neuropathy, and Hyperglycemia, which are, you know, some of the typical side effects that we see with informabdotin. Um, you see on the right hand side, about 42% of patients had grade 3 adverse events, mostly related to cytopeniaas or LFT elevations. Um, so this novel combination is being evaluated in a phase 3 study in China compared to platinum-based chemotherapy. Um, again, I think it's going to be a high bar to reach based on the previous data that we've seen with EV Pembro, but certainly calls into question, are there other nectin for antibody drug conjugates, um, which may have different adverse effect profiles relative to what we see with EV Pembro. Last but certainly not least, we'll talk about SA2's Mabrovotekin, and as many are aware, um, SG is an antibody drug conjugate against TOP 2 with a SM 38 topoisomerase payload. Um, it was initially received accelerated FDA approval in the Treatment refractory setting for metastatic urothelial cancer. However, we saw the TOX 04 study, which was supposed to be the confirmatory phase 3 trial, um, which did not show an improvement in overall survival for statutesab go T can relative to chemotherapy and actually had relatively high rates of, um, grade 34 adverse events and the number of deaths. And so, this actually led to the voluntary withdrawal of the accelerated approval in metastatic urothelial cancer for this drug. Um, prior to that being done, um, there was this javelin bladder megaley study that had been launched years earlier, and this investigated patients who had received frontline, um, cisplatin-based chemotherapy and had either stable disease or partial response. Those patients then went on to either receive a Vellumab, which was our kind of standard of care in this, um, in this setting prior to EV Pembro, or various combinations of Evaluab plus other agents. What this abstract highlighted was patients who were randomized to receive Abelumab plus me over T10. Um, what we saw was, um, a majority of patients, so about 75% of patients had a response to frontline platinum-based chemotherapy relative to about 25% of patients who had stable disease when treated with first line platinum-based chemotherapy. And the study actually met its primary endpoint. So we see an improvement in progression free survival of PFS of just 3.7 months on a Valab versus 11.1 months on Vallumab plus SG with a hazard ratio of 0.49. Overall survival is immature at this time, but you see, again, those curves are are very close, um, in between two treatment arms with a haz ratio of 0.79 and a confidence interval that crosses over one. we did see much higher response rates to SG plus a valuab at 24% versus just 2.7% on a valuab, um, higher disease control rate and prolonged duration of response to SG plus a valueab. Um, not surprisingly, um, the combination did have higher rates of grade 3 adverse events at 70%. Uh, 50% of patients had to have SG, um, dose reduced, and about 50% of patients received concomitant GCSF with SAS 2 snapva Tan. So, Some of the takeaways, obviously this is a um a positive study that showed an RPFS benefit to using Satuzumab earlier and using it in combination with a PDL one inhibitor, Evaluab, um, certainly had some treatment related adverse events and dose reductions to deal with, um. But at the end of the day, I think it tells us that stuzumab Gobin is an active drug, and it's up to us to try to find, you know, a combination or a setting in which we can use this drug more effectively. And that is part of the concept behind the dad IO study, which is um the Um, second generation of study led by our own Brad McGregor. Um, Doctor McGregor initially did a phase one study of EV plus SG, um, which showed high response rates for patients with metastatic urothelial cancer, and so theAIO study is investigating the triplets are SGEV and um pembrolizumab for first line treatment of metastatic urothelial cancer. The study is open and we certainly look forward to enrolling patients on this study. With that, I'll invite Doctor McGregor on um for his expert commentary on our bladder cancer abstracts. Yeah, great, uh, presentation. I think overall, I think it was more practice, um, reinforcing that practice changing when we look at what was the bladder as starting with the SG, I don't think it's really the comeback kid. Um, I think that, you know, SG really, its role in bladder cancer is gonna be difficult to identify. I think TOP 280C certainly have a role, and I think the data that we saw from Java Medley, with their unusual statistical analysis does highlight that SG can play well. With immunotherapy and to Mike's point, I think that this is not going to be used as a monotherapy. The dose of 10 was the wrong dose without GCF as a on approach. And so as we think about, um, where this is gonna work, it's gonna be judicious use, making sure we're really aggressive with supportive care. And so if we look at the data of your trial, which is open, I think that EV tempo is a great, um, regimen. Can we do better? And so we're looking at SG and just to highlight, we're using lower dose SG, so 7. 5 on day 18, not 10, and we're pretty much mandating GCSF if recommended for as islands, which if you look at bladder cancer patients, every patient with bladder cancer meets the criteria for GEF for la we look at a regimen like SG and now suppression. So I think it'll be interesting to see. I think it is open, um, and I would encourage any patients getting EV Pembro. um, we can think about doing this trial, um, for them we are really high responses with um SGEV. In terms of that from EB Pembro, as I think as one of the commentators said, it was like it's the lap. Um, so I mean, ED Pembro is incredibly active. I don't think there's any doubt about it. I mean, median response over two years is just again, it really just spell the end of. Platinum eligibility, I think that's the key point like we should not be looking at set up what we're going to use EB Pembro or platin Nero. I mean the EB Pembro is just way to canal 30%, um, CR rate, 70% response rate, I mean. It's just, that is the new standard of care. I think I mean might brought up a lot of interesting points about who can we de-escalate and all those things. I think that's gonna be really tough to do a randomized trial because no patient we've seen um from efforts by Doctor Wai try these DSs is incredibly challenging. You have a standard of care and by the time you can convince a patient that was echo poison responding and reducing or holding like, well, why don't I put up the chance? I just want to do that anyways, right? So I think um this is gonna be the challenge we look forward to the future. And I think as we look forward to the future, the novel ne4ies are gonna be coming. So I think I mean, ED time is great. Can we do better than ED? Um, can we adjust toxicity problem improve efficacy? I think the small trial from China is the first, but I think there's gonna be many more nin for EDC development, as was come out, questions can we use that in sequence, replace EV. And then finally, the role of CTNA, I think, you know, this was really interesting data. I think it shows that CTNA is going to be an additive um prognostic tool to what we already have. I don't think we replaces anything. So if we look at the data overall, CTNA positivity was or prognostic marker at every single point of the patient journey, pre-therapy, pre-cystectomy, post cystectomy. I think what is interesting is you saw that, you know. And that increased clearance of CTA in a pre-operative setting. We saw that some patients cleared their CTA just with surgery, all right, and that led to improved outcomes. And then more importantly, at the end, you know, past CR and CTA, they both played a role. If the patient with CTA negative, but did not pass CR, they had a worse outcome than the patient with CTA negative and past CR. And so I think it's gonna be, this is the first that I get this person have to look. Um, I think the modern trial is incredibly important. I mean, as initially it was designed, can we look at it as a um escalation trial and those patients who got this genderva have a great response? Can we maybe do better by doing Nearella? Can we de-escalate? So I think it's going to be continue to answer a lot of important questions. I think we really need to support that. I think hopefully we'll start seeing CTA like we did here in Agra, move into the metastatic space and maybe that can be a space we can start thinking about how we can deescalate the cover. Fantastic. Thank you, Doctor McGregor. I loved your um your analogy to just the victory laps of uh all these regimens and, you know, looking towards the future and how, how we can potentially improve on, um, the success of these regimens.