Chapters Transcript Video 2026 ASCO Bladder Cancer Highlights The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the bladder cancer clinical updates In the interest of time, we will move on to uh bladder cancer, um, where we'll be joined by Doctor Bauman for our discussion and, um, less to cover here, but I think um some really important insights that we gleaned from the ASCO 2026 meeting for patients with bladder cancer, we'll start with non-muscle invasive disease, move on to first line metastatic, and then the refractory disease setting. And again, we know that um for patients with non-muscle invasive bladder cancer, the standard of care for many decades has been um BCG induction followed by maintenance therapy. Unfortunately for those patients who do not respond to BCG, um, we're often looking at either a cystectomy or a clinical trial, and in certain circumstances you see on the right-hand side giving pembrolizumab, the anti-PD1 systemic therapy for Those patients. Um, there have been 3 large randomized phase 3 trials that have reported over the last year using various combinations of either anti-PD1 or anti-PDL1 therapy in combination with um BCG for patients with non-muscle invasive bladder cancer. And this is um taken from Dr. McGregor's excellent discussion at ESO. We know that the Potomac study, which use the PDL1 inhibitordervalumab with um BCG induction and maintenance, met its primary endpoint, improved event-free survival. CREST, which used the subcutaneous PD1 inhibitor, sisanolimab for 2 years, um, with BCG induction and maintenance. Also met its primary endpoint with an improvement in eventree survival. However, ABI, which was the study of tezollizumab, did not meet its primary endpoint. So we have again two positive studies for EFS and one negative study. There were slight differences in the inclusion criteria, um, and how these studies were run, as well as the long-term follow-up. Um, but, you know, it stands that this is a, um, increasingly complex space in non-muscle invasive bladder cancer without, um, a real standard of care. Um, it's into this space that we saw an update from the Potomac study. This was The 5 year OS and patient reported outcomes um that were reported from the study. Again, as a reminder for folks, this was for patients with non-muscle invasive bladder cancer who were BCG naive and had high risk disease defined as T1. Um, high grade or, uh, CIS and having multiple, uh, or recurrent large tumors greater than 3 centimeters. Patients were randomized in a 1 to 1 to 1 fashion to dervalumab plus BCG induction and maintenance, Dvalumab plus BCG induction alone, or BCG, uh, induction and maintenance again without the durvalumab, primary endpoint looked at disease-free survival, secondary endpoints looked at. OS, um, again, this has been reported previously, but we know that, um, the durvalumab plus, uh, BCG induction and maintenance improved, uh, disease-free survival with a hazard ratio of 0.68 relative to the BCG induction and maintenance with the median. of 60.7 months. The data that we saw at ASCA 2026 was the five-year overall survival, and you see that those curves are essentially overlapping for the entirety of the curves, and that has a hazard ratio of 0.81. With a median follow-up of 72 months. So again, Durvalumab did not improve overall survival. Um, they did report out the cystectomy-free survival, this is data from the AUA 2026 reported by Doctor Neil Shore, um, and it did show an improvement in cystectomy-free survival with that hazard ratio of. 0.69, although I will note that there were a very small number of patients in either arm who had cystectomy, only 34%, only 34 patients total out of a study population of nearly 700 actually had cystectomy, so hard to maybe overinterpret that small difference between the treatment arms. Um. And then the second part of this presentation looked at um patient reported outcomes and essentially saw no difference um with the addition of draumab relative to BCG alone. And so, um, in, uh, into this context, we also saw a FDA approval fordraumab plus uh BCG for high-risk non-muscle invasive, uh, bladder cancer. This was Uh, FDA approved on May 28th, 2026. Um, you know, what are some of the takeaways? Well, again, we know that the study did improve DFS, did not improve overall survival, and there was no change in health-related quality of life. Although maybe there was an improvement in cystectomy-free survival, the numbers are very small. And so I think for me, and for, you know, I think a lot of our urologists, um, it's, um, Like anything, I think gonna come down to a careful weighing of the potential benefit of adding dervalumab to BCG for patients with non-muscle invasive bladder cancer versus the very real risks of uh anti a year of anti-PD1 therapy and the impact that that can have on our patients' quality of lives. I've heard, you know, a couple of different arguments, maybe for that patient who is very elderly, where you want to do everything possible to avoid a. that patient may be a candidate for uh the addition of durvalumab, um, but, you know, hard to see how this is gonna really, um, make its way into our clinical practice, and then how we're gonna potentially co-manage these patients, whether it's urology or medical oncology, giving the anti PDR1 therapy. I think a lot of logistics need to be worked out, but, you know, now knowing there is an FDA approval for this drug in this space. Um, the second abstracts that we'll go over is the, um, long-term follow-up and complete responder assessment for patients treated with EV Pembro on EV 302. Um, as many on this call know, EV 302 is the large randomized phase three clinical trial, which, um, showed that EV Pembro improved outcomes relative to our previous standard of care chemotherapy. This was the 3.5 year follow-up and, um, assessment of patients who had a complete response, um. As just to serve as a reminder, this is for patients with metastatic urothelial carcinoma who were treatment naive, um, and eligible for uh PD1 therapy. They were randomized to either EV Pembro until, uh, treatment until progression or chemotherapy with Gem Gemy or gemcarbo with a maximum of 6 cycles. And, um, again, we know that this study improved, um, outcomes. This is the updated OS that we saw, um. With uh uh about 3.5 year follow-up, we saw the um hazard ratio for OS benefit was maintained at 0.53, and again a doubling of median overall survival from 16 months with chemo to uh just north of 33 months with EV plus Pembroke. Um, we saw that, uh, doubling of the complete response rate from 15% with chemo to 30% with EV plus Pembroke, and when they look at the CR evolution, you see that, um, the patients who had a primary CR, so a CR on their First assessment that was 10%, whereas um patients who had an evolution from CR to PR that was about 20%. So looked at looked at another way, um, patients were more likely to have a partial response that converted to a complete response than Um, then have a CR directly, and they looked at the dynamics, so the time to CR, um, in patients who had a complete response was 4.3 months, and then those patients who had a conversion from partial to complete response that took a little bit longer at a median of about 6.6 months. Um, when they looked at those outcomes between the groups, whether patients had a primary CR or a conversion from PR to CR, again, you see, um, between those two, the outcomes were similar. And then, um, the time, uh, the time when patients were on, uh, EB plus Pembroke, you see as patients were on therapy for longer periods of time, they had higher rates of treatment-related adverse events requiring more frequent dose reduction. I, I think this is intuitive for many of us who have been using this combination. Um, interestingly, when they look at lines of subsequent therapy, so patients who had progression of disease after EV Pembro, um, patients who are treated with platinum-based chemotherapy had a response rate of about 20% with a median overall survival of about 11 months. This is, I think, some of the earliest data that we've seen of, um, using platinum after EV plus Pembro, and on the right-hand side again, you see not much of a difference in response rate between whether patients got cisplatin. Or carboplatin as their platinum in a subsequent line of therapy. I think this, you know, may be um something that we think about as we evaluate, you know, post EV Pembro response rates, um, for patients who have progression. So, again, at some of the takeaways at 3.5 years of follow-up, 44% of patients initially treated with EV Pembro are alive, 30% of patients had a CR and 10% had a primary CR, whereas 20% had a conversion. Um, I will note that patients were treated until progression, and so for those patients who had a CR at 4 months or converted from a PR to a CR at 6 months, were we overtreating those patients? Are there opportunities to use things like CTDNA to potentially de-escalate therapy for those? Exceptional responder, uh, those patients who are exceptional responders, and then for those patients who have progression after EV Pembroke, I think platinum is probably our default standard of care, but is there an opportunity to potentially sequence ADCs with, um, changing either the target or the payload. And that's gonna be our, our last, um, uh, set of abstracts to discuss is, um, opportunities and challenge and challenges in sequencing ADCs, and this slide was taken from a poster, um, that was done out of uh Sloan Kettering in New York, where they took patients who had EB Pembro and had progression of disease and did biopsies and stained that tissue for nectin 4, trope 2, and HER2, and as you see on the top, um, patients had Um, that, uh, membranous nectin 4 remained highly expressed post EB Pembroke, but also trope 2 is rather highly expressed post EB Pembro, and even HER2, there was a moderate expression, maybe about 40, 50% post EB plus Pembrose. So I think this is, you know, some tissue evidence that perhaps, um, you know, nectin 4 remains a viable target after EV plus Pembroke. That we may have other um uh targets that we can use ADCs for after uh progression on EV plus. Pembroke, this is a slide taken from the Eur Amigos, but obviously there are a lot of ADCs in development in urothelial cancer. Um, broadly speaking, you know, we have 3 targets, either nectin 4, trope 2, or HER2, maybe HER3 and EGFR emerging, um. Two payloads, either MMAE or topoosamase one, and obviously different linkers as well, whether they're cleavable or non-cleavable, I think probably um bear out on the tolerability of these drugs. Um, again, our NCCN guidelines tell us that we should be using these biomarker-directed therapies when. Applicable. We do have a label for TDXD and I'll note that the most recent NCCN guidelines not only include patients with HER2 by IHC 3+, but also IHC 2+. Again, I think a lot of us who see patients with this disease are able to get um the TDXD approved for our patients with metastatic urothelial carcinoma. So, Um, the next two abstracts are gonna be, um, looking at data for nectin 4 ADCs in, um, advanced or metastatic urothelial carcinoma, the first of which is the Nexus 01, the LY 405-2031 drug. And this is based on understanding that we know um EV resistance may be mediated by um a payload efflux, and so the thought is, should we maintain the target of nectin 4, but rotate a different payload in to try to improve the efficacy after progression on EV. And I will note that this um molecule investigated on this study is um a topoisomerase1 inhibitor camp 98, and that camp 98 is predominantly uh cleared by the liver and SIP 2D6. And this is the design of the Nexus 01 study. Again, this was a dose escalation and optimization. This um uh random this included patients with advanced or metastatic tumors known to express nectin 4, and prior EV was allowed on this study. And as they went along, they found that there were some patients who had a very poor tolerance of this therapy, so they opened up a substudy where they looked at the SIP 2D6 activity score, and um for those patients with an activity score. 0, had a lower dose, so 1.2 meg per gig, and an activity score of 0.25, they had a higher dose of 2.4 megs per gig, um, because they found that patients who had an activity score of 0 actually had a much higher risk of severe toxicity on this drug. And patients who enrolled in the study, again, there were 137 patients total, 107 of which had metastatic urothelial carcinoma. You see, um, relatively small numbers of patients with uh SIP 2D6 activity scores of zero. There were only 3 patients, and 0.25, there were only 5 patients. The vast majority of patients had that activity score greater than 0.5 or 92%. And then in the uh urothelial carcinoma cohort, you see about 90% of patients had prior platinum chemotherapy, 2/3 of patients had EV either with or without pembrolizumab, and actually 20% of patients had a prior topoisomerase1 EDC therapy. Um, when we look at the adverse effects associated with this drug, we see, um, the most common were low grade alopecia and nausea. We saw low rates of EV associated adverse effects, so again, low rates of things like neuropathy, ocular toxicity, hyperglycemia, uh, much more. Pin we saw hematologic toxicity. So anemia again across dose levels, um, as the dose increased, um, we saw in the highest dose level, uh, grade 3, adverse event rate of anemia of 25%, mukocyte is 13%, and neutropenia of 17%. And again, I think the SIP 2D6 activity score really tells a very intriguing story. So those patients who had an activity score of 0 had much higher rates of mucositis, neutropenia, febrile neutropenia, and sepsis, over 50% of patients, whereas those patients with an activity score of greater than 0.5, we saw the grade 3 adverse events in those categories, all less than 5%. Again, telling us that the SIP, the SIP 2D genotyping really does um tell us what the exposure to the drug is and thereby the risk of adverse effects with this therapy. And then when we look at efficacy again, small numbers, but in the 48 patients who were topoisomerase naive and had a SIP 2D6 activity score of 0.5, we saw a response rate of 42%. Those patients who were post EB had a response rate of 33%, and those patients who were EB naive had a response rate even higher at 67%. Again, disease control rates all greater than 75%. The last thing to note is that um of the 20% of patients who had prior topoisomerase 1 ADCs, none of those patients had response to therapy. I think again, telling us that using the same target of nectin 4 with a different payload, um, is a feasible approach, but using um a different target with the same payload, um, likely is not going to garner benefit. Um, and then, uh, the last, um, the last thing I'll look at is the, uh, the durability of response where we did see a mean duration of response of 7.4 months among, um, patients who responded, and about 2/3 of patients had responses ongoing in the TRSamrase uh naive SIP 2D6 AS greater than 0.5 cohort. So, Again, I think this is really intriguing data and um supports the idea of sequencing ADCs um using the same target of nectin 4 but a different payload. And I, I think again the SIP 2D6 genotyping tells a very intriguing story that, um, that for at least for this drug, that um is a critical import uh an important way of understanding what the dose exposure is going to be to this, um, to this drug and the risk of severe adverse effects. Um, the last abstract we'll go through is the exceed study. This was, um, also an antibody drug conjugate targeting nectin 4 with the topoisomerase 1 payload. Um, this was presented by Doctor Jin Gao, one of our colleagues over at MGH. Again, almost identical. Background slide to our previous drug, uh, and again, this was an ADC targeting nectin 4 with a topo 1 payload. This also included patients with solid tumors known to express nectin 4 and prior EB was permitted on this study as well. Um, they, um, I, I will note, you know, the patients enrolled on this study, um, did appear maybe a little bit sicker than the previous one, so there were 143 patients in total, 86 with metastatic urothelial cancer, over 90, almost 90% of patients had visceral metastases, about 90% of patients had prior platinum, and 92% of patients had prior EV with or without pembrolizumab. And what we saw from this drug, at least from a safety standpoint, was that there were relatively high rates of grade 34 adverse events, so anemia was 52%, neutropenia 31%, thrombocyteenia 24%, often requiring dose reductions or dose holds, um, and, uh, they did not have many EV associated AEs, but again, I think the Borisomerra one payload has different adverse effect profile than what we saw with EV, um, in terms of response rate, um, in the, um, responses were relatively modest, I would say, you know, in the total cohort was about 20%, and then as we dose escalated, we got all the way up to 36% with the highest dose level, um, again, uh, disease control. Rates anywhere from 58 to 78% across cohorts. And so, what do we take away from this? Well, I, I think this drug shows modest clinical activity, um, you know, a response rate of about 20%. This drug did have much higher rates of grade 34 chematologic toxicities, whether that's related to the payload, whether that's related to the prior. You know, platinum and prior EV exposure, I think it's, uh, you know, maybe brings a little bit more caution to when we're sequencing ADCs, we really do have to think about those hematologic toxicities considering GCSF after our experience with this drug, but also with testacituzumab gobotecan, um, where we saw relatively high rates of hematologic toxicities. So, um, And there are, uh, notably a number of trope 2 targeting ADCs under investigation. We know about SG, there's DDXD, there's uh SACTMT, and we do have, um, several protocols that are either opening or soon to open here at Dana-Farber, investigating novel ADCs for patients who have already received EB plus Pembra. So with that, I will close and ask Doctor Belmont to uh join us for his expert commentary. Uh, yes, my, yeah, excellent summary. Uh, in fact, uh, as we have seen, there was nothing new, exciting, uh, changing the standard of care, but yeah, it was, uh, updating some trials that, uh, have already been presented, so that I will go, uh, to comment that the, the highlights of these, of these trials. So the, the first thing is the Potomac. The Potomac, as you have mentioned, benefiting even survival like the, the crest that is using a soundly map. The point is that um this, this was FDA approved, um, the other one has not been filed, and, um, and the reason behind when, when you, you, you ask is that they were looking for other endpoints in the crest. Uh, because people is meaning this, this is approved, but the people are not using these, uh, combinations of, uh, of, of BCG and, and Iotherapy because the population of patients that might potentially benefit, it is not identified, and these only 34 patients having a cystectomy showing a cystectomy pre survival. This, this, this is really a, a, a, a, a main endpoint on, on this, on this type of trials, and, uh, as mentioned. Um, even in the guidelines, I, I'm involved in the, in the ESMO guidelines, there was a lot of debate, and, uh, Maria de Santis is in the guidelines, so there was a lot of conflicts here, and they, they finally say, well, it's the urgent option, but without defining where are we going to use or which spaces are we going to use the, the, this combination. So just mention that the, the, the crest family map that is the same concept, um, they have to not apply as FDA, meaning that because people saying that they might be waiting for more strong, uh, endpoints. So the, the, the second group about the, the, the EB 302, I think that that's, that's really important because in this trial, for example, they did show that 23% of the patients received treatment for two years and then the question is. For how long do we need to to treat our patients and the issues on when to stop the long term toxicity has not been addressed. Obviously they, they provide this relevant information that uh in the end, 80% of patients were alive at at 3.5 years. Either the same benefit observed in patients getting the CR or the ones that from CR end up on, on developing a CR. So I think that's, uh, but I think that in this presentation, the most uh interesting thing is like for the first time is, um, the, the, the value of platinum agents is being, uh, reported in patients post EVP. We are using extrapolate and say, well, uh, platinums inside bin or carboplatinums inside bin was useful in first line. Why not to use it after EVP? But we see here that only 29% of patients received carboplatinum or cisplatin in this in this trial, and this was selected patients in a clinical trial and only 20% of response rate with a median duration, median survival of 11 months that is not, uh, but meaning very few patients likely derive benefits. So and. That I believe that, yeah, so we're going to see that uh there was the reports of the phase one of PVP showing that 40% of patients are alive at 5 years. So we're going to see more and more patients being alive at 5 years, and I think that's, that's an important, um, yeah, data, uh, report. But I think that the most exciting uh was these, uh, these new ADCs and uh just to summarize, interestingly, those were the Nexus one and the exceed were uh Lily compounds. And uh in one, the nexus one, you have reported that this, they, they use this, uh, this need to genotype the patients just to uh uh see that much better benefit, the, the, the SIP to the, the 6, and the main difference is like the, the, the payload in one is CAM 68 and the other one is ecstatican. And in one, the, the linker is a peptide cleavable linker peptide, and the other one is a polysarcosine. I, I don't know exactly what chemical, but based on that, one is really much more effective, um, and there is not that much myosuppression, but in the other one, in the exceed, the one that Gao presented, so the response rates were not that high, 20%, even maybe different patient population, but the, the, the toxicity, even adding GCSF, they were unable just to reach the recommended dose level. And obviously one of the best lectures that we, we, we got from these two trials is that it seems that we can reuse the target as you have presented, but when you reuse the payload. Response rate on the Nexus 01 is 0%. So, and that's an important thing, and it's good that you have presented this, this, uh, this, this, this study from, from Memorial, the Empire where they have been looking what's happening with the, with the markers, uh, after, um, the patients with EVP. I think that's the, the main summary, and I believe that this compound likely in action is going to move forward. Um, another thing that, uh, interestingly, obviously you don't see skin toxicity, ocular toxicity, hyperglycemia with this. In fact, it's an, an anti-nein form with a top one inhibitor. And then one thing that I asked to the, the, the presenter to the Copa Iyer is that the, the pulmonary toxicity was not as high as, um, as, as, as an inheritance because I said, well, I have a patient that I sent to him, and well, he was cow, and he said, oh, prior ILD, those patients are not eligible, but they saw a, a, a, a lower rate of, uh, of pulmonary toxicity with uh, with this, uh, Naxus compound Lily number X, all right. So those are my, my comments. Just we are running out of time, so we can move ahead with, uh, with Kimmy. Thank you. Yeah, yeah, no, I appreciate it, Joakim, and, and I completely agree. You know, finding where Draumab fits in non-nasal invasive disease, you know, a, a really open question. I, your point about the long-term toxicities associated with EV Pembro on 302 are, are notable, and I, I would have loved to have seen that data presented as opposed to the complete responders who we know those patients do well. Um, and then as you mentioned, you know, not all of the ADCs are, are similar. There are very notable differences between them, and I think that's really the next frontier of what do we do for patients after EV Pembro, and, and, you know, I'm excited to have you down the hall to ask questions on, uh, on how to use these drugs moving forward. Published July 1, 2026 Created by Related Presenters Michael Serzan, MD Medical Oncology View full profile Bradley McGregor, MD Medical Oncology View full profile
