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 ASCO 2024.
Thank you all for joining this evening for our as o annual meetings. Uh highlights of 2024 moving right along. Um We'll move on to bladder cancer again before we dive into the data. I think it's important to have realized that 2023 was a really important year for bladder cancer. We saw two large phase three trials with EV Pembroke Cis Nevo. Um really take the place of CISplatin based chemotherapy in the first high metastatic setting, which had been the standard for greater than 30 years. Um We also saw data supporting the role of A and pembrolizumab and the Bachelor study that was presented at Gueo this year and then a new FDA approval for a her two targeted therapy for patients um with uh with um in the advanced disease setting. So I think a lot of exciting work um in, in bladder cancer. And um and with that as our background, we'll dive a little bit more into some of the abstracts from. So 2024 um the first study that we'll discuss is uh patient reported outcomes from the EV 302 study. Um So this is the study that I was just referring to uh inform A plus um plus pe V plus PMB um compared to platinum based chemotherapy for her sign metastatic opel cancer. The primary endpoint of this study was looking at both PFS and overall survival. And then there were some very key secondary endpoints that this abstract is focused on um for anybody who, who isn't aware. Um We saw this data presenting back in the fall um where EV Pem bro um met its primary end points of pfs and OS with your doubling of progression free survival at 12.5 versus 6.3 months and overall survival at 31.5 versus 16.1 months. Um And with this, we also saw that EB PMB um was generally well tolerated, did have higher rates of neuropathy rash relative to chemotherapy, which had our kind of standard um cytopenias that we expect to see. And so what this um ABT was focused on was looking at patient reported outcomes and a couple of different domains. So, cancer related symptoms, function quality of life. And then um and then any difference in pain in one regimen versus another. Um There was uh one of the key secondary endpoints was looking at time to pain progression. And as we see here, there was absolutely no difference in time to pain progression on ebro relative to chemotherapy. Um And that's somewhat surprising if we um believe that Ev Pembroke is such a better regimen as far as um improving PFS and OS. But then we also have to think about only a third of patients actually ranked that they had a baseline level of moderate to severe pain. And so perhaps it was just hard to see the delta difference between the two treatment regimens. When we focus on those patients who did have moderate to severe pain. At baseline, we see that um within about three weeks, we see an improvement in um in that worst pain level on both regimens. But then after that, we see EV Pembroke in blue, that line actually shows a clinically meaningful improvement in um in worst pain uh on that regimen relative to chemotherapy. The second outcome we'll look or the third outcome we'll look at is global and global health status or quality of life score. And we actually see from baseline on both regimens, we see a transient worsening of quality of life, whether patients got chemo or EV plus Pemra. But then eventually after that three week point ev um rebounds back to baseline and is maintained there. Whereas chemotherapy, there was a um a clinically meaningful worsening of quality of life throughout the duration of the trial, which I think makes sense to us. Patients don't um don't enjoy being on chemotherapy. Um lastly, we'll look at um functioning domains. So physical functioning, social functioning, cognitive functioning, all of those domains favored EV Pemra relative to chemotherapy. Um And so in conclusion, we see that obviously, Ev Pembroke has excellent pfs and OS outcomes and that the patient reported outcomes I think of are very much a supplement to that data telling us that patients are tolerating therapy. Well, um and that um and that their quality of life is improved or maintained while on this regimen. Um The second abstract we'll look at is, is one that I, I think is really important and one that I've, I actually cited in the last couple of weeks when I've been treating patients in the clinic and this was looking at the impact of exposure on outcomes for patients treated with important epi doin um in advanced kidney cancer, in advanced cancer. And when we look at what this analysis did was look at patients who were treated across three different trials. So ev 101 which uh treated patients at with ev monotherapy across several different dose levels. And then ev 201 and 301 which treated patients on EV monotherapy at our standard dose of 1.25 mg per kilogram. And what we see was that eev monotherapy has remarkably consistent activity across all different uh all of these different cohorts with a response rate anywhere from 40 to 50%. Uh median progression free survival of about 5.5 to 6 months and immediate overall survival of anywhere from 12 to 15 months. Um We also see that um uh that eb monotherapy was managed what was well tolerated um with a uh treatment related uh dose reduction of anywhere from 30 to 40%. A treatment related um adverse event rate causing discontinuation and anywhere from 12 to 15%. Um The most common reason for um either dose reduction or dose continue discontinuation was due to peripheral neuropathy. And I think that's something that we're very used to seeing in the clinic even uh as we have early evidence using this drug. Um the the next analysis looked at um the higher early ev dose intensity was generally associated with a greater probability of response. And so that was across cohorts and these are looking at different quartile of dose intensity. So quartile, one is the lowest dose intensity, quartile four is the highest dose intensity. And logically speaking, the more the higher dose of pat of EV that patients got early, the better they tend to do. As far as um initial response rates. We saw that pro protocol recommended dose reductions were used to manage uh adverse events across studies. And we see that that those rates were anywhere from 30 to 50% um across all of these different cohorts that were analyzed. And when we pull all of these studies together, we see that early on many patients were able to maintain that dose of EV at 1.25 mg per kilogram through cycle seven. But that after that seven cycle, we started to see more dose reductions as time goes on. And then at the far end of the graph, you actually see increases in ev doses. Um but when you realize that there's very a few patients who are on that part of the graph. And so I think it's just relatively speaking, some patients were able to maintain a dose longer. It wasn't that they were then subsequently increased. The other really important part about EV is that um actually dose dose reductions, dose delays um were actually ok. So this is looking at a swimmer's plot of patients who are responding to therapy. And as you see, there's a lot of white space in between these lines. And so that's time when patients were off therapy. However, they continued to garner response from this comin from, from eev as they went along. So I think that's really important to, to be able to say that to patients and, and to be able to counsel them as we're talking about those reductions, we then looked at median duration of response again by quartile of strength of EV given. Um And again, the duration of response was largely similar across all quartile. So anywhere from 5.5 to 7.5 months. So in conclusion, again, a higher uh dose of EV at the beginning um seems to correlate with a greater likelihood of response to therapy. Um dose reductions are ok. And uh and dose delays. Um do not seem to impact the duration of the durability of response from EV monotherapy. Um One of the really interesting things is to think about, well, what happens when patients experience disease progression on ev one of the next um logical treatment options is to think about um sequencing a second antibody drug conjugate. So S tous and that go T can is an approved regimen in the second line. And this was a retrospective analysis done by the folks down at Memorial Sun Kettering of patients who got EV plus, who got EV and then got SUSE AB go T A and actually showed pretty dismal responses. So our response rate of only 11% and median progression free survival of 2.1 months, media overall survival of six months. Um And so I think really calling into question at this paradigm of trying to sequence AD CS one after another. And so if sequencing is um is perhaps less desirable, is there a way that we can combine AD CS? And this was a study not presented here at this A O but presented within the last year, the D A study which was led by our own Brad mcgregor as well as many other folks in our group which was combined in satu A goo T can plus and for the, and what we saw was um really impressive efficacy outcomes with a response rate of 70% uh A twelvemonth progression free survival of 41% to 12 month overall survival of 86%. Um The regimen did have some toxicities, mostly cytopenias that were managed um either with those reductions or giving G CS F. Um And so kind of on the heels of the dad study. Um there was a trial in progress poster presented by doctor uh doctor mcgregor, which is the next step of this, which is the Dad Io study, which is combining SAST and use me goin um in for a doin and pembrolizumab as a first line treatment for patients with metastatic ethel cancer. And that is a study we're looking forward to having open here at DNA Barber as a first line option for patients with um el cancer. Um The next study we'll look at is a character of complete responders on the checkmate 901 study. Um So, as I alluded to this, uh there were two really groundbreaking studies that came out in the fall. This was the second of those which was checkmate 901 which randomized patients with firstly, metastatic ero cancer to genesis Nebo uh relative to genesis. And then, um and, and what we saw from the study, we know that improved progression free survival and improved overall survival. Um But one of the big questions that we've had is are there any particular subgroups of patients who may benefit from GSIS Nevo um relative to EV Pemra? Um And so what this analysis did was looked at those patients who had a complete response to therapy and that was about 16% of patients. Uh And it looked at, are there any particular features that are enriched in this population? And what we see is in all randomized patients? On the left hand side, there was about a 20% of patients had lymph node only disease. Whereas uh the patients who experienced a complete response, that number was much higher at about 52%. Suggesting that this is a uh a novel biologic subgroup of patients with metastatic urothelial cancer. Um who may have an enriched response to um GSIS Eva. And so when we look at that data a little bit more closely, we see again, on the left hand side, this was the I TT population with a response rate, 57%. A complete response rate of six of 21% in the lymph node only subgroup. That response rate is much higher, 81% and a complete response rate of 63%. Again, small numbers, but really an intriguing signal to see there. We saw that that increase in response rate was also translated to a an improvement in progression free survival with a medium pfs. On in the lymph node only disease subgroup of 30.5 months relative to 8.8 with genesis alone. And then overall survival similarly improved. Uh with genesis, we also saw that gem cis Nevo. In this lymph node only uh population was able to achieve treatment free intervals for uh uh uh a substantial portion of patients. And so, in summary, um you know, this is really intriguing data uh that this time limitted therapy of gem cis Nevo. Um in this biologically defined subgroup of lymph node only um urothelial cancer, this may present a treatment option for those patients. However, um as the discussion, very aptly pointed out the elephant in the room is how did those patients with lymph node only disease do on EV Pembroke. And on the left hand side here, we see the response rate to EV PMR in the lymph node only disease group was 77%. Again, that's compared to 81.5 we saw with temps Nevo. And similarly, we see a really impressive overall survival in lymph node only disease and patients treated with EVP. What's more um this I I if um we also have to ask, how were patients imaged? Um were patients getting just plan CT scans? Were they having pet scans done? Did we maybe underappreciate um evidence of distant metastatic disease if patients get CT scans alone? And so I think certainly some more work to be done to better define this population. Um So again, in summary, lymph node only disease um seems to be a favorable prognostic indicator. Um I think in my practice, I would probably discuss the merits of both EV Pembroke and Genesis evo with individual patients. Um but would be excited to hear what Doctor Belmont has to say after our next abstract. Last but certainly not least we saw um evidence we saw data on resus map Dire Toan, which is a her two targeted therapy from the pan tumor 02 study. Um This was data presented previously, but there was a poster specifically on patients in the bladder cancer cohort. So this was a pan tumor um analysis and um we saw that there were um 41 patients in the bladder cancer cohort and this eventually led to uh FDA approval in April of this year. And again, what this um with this post were analyzed was specifically those patients with bladder cancer, of which there were 41 patients um patients um were at base at enrollment. What we highlight here is that um they were three plus on enrollment, that was 65% of patients. But then when they had their her two testing done centrally, there was a difference and that um that was about a 25% difference between IHC red locally and IHC red centrally. Um We see that a majority of patients in this cohort again had received prior um uh IO based combinations. And um when we look at efficacy outcomes by her two status, we see her two IHC three plus had a response rate of 56% of median progression free survival of 7.4 months and immediate overall survival of 13.4 months. Um In the her two iht two plus population, we see a relatively lower overall response rate of 35% but actually similar median PFS is of 7.8 and 13.1. Um We saw trastuzumab Doan was actually pretty well tolerated. It did have a, a grade three, a four adverse event rate of about 40%. Um with about 10% of patients uh discontinuing due to toxicity not listed here, there was a 10% rate of interstitial lung disease on this therapy. So certainly something to be mindful of before diving in with resus dere Toan. And so again, this um represents a, a new treatment option for patients who have been on standard treatments and experienced uh disease progression. We've had a lot of internal dialogue with our pathology colleagues about it's not really feasible to get her two testing done on every patient, but certainly for that patient who um who needs a subsequent line of therapy. Um I think getting a, a biopsy and repeating her two testing at the time, close to the time when they may need therapy is a feasible approach to take. Um And again, this has now made its way into NCCN guidelines and is um AAA standard of care option for patients with advanced disease. So, um again, with that, I'll, I'll close and thank you for your attention in the bladder cancer space and um ask Doctor Belmont for some of his comments and discussion. Yeah. Yeah, excellent presentation summarizing. Um Yeah, the most interesting and abstracts presented at OO So again, as Tony said, so um also there were no so many exciting new data for Blader though all of those, those abstracts were like uh um subset analysis or sport talk analysis. But uh I think that's of relevance is that this analysis on the EB trials about exposure um that you need, you need to follow the the the guidelines on the on the dose intensity in the very beginning. And then it's good to know that uh adjusting the dose that's not compromising the the future. I think that's a very important message on this. Uh they put together the phase one, the phase two and the phase three. So the it was, and they were analyzing the pated and in the first two cycle. So I think that that was really, really interesting for the patient reported outcomes. I was expecting to see more data on um narrow toxicity, for example. Yeah, it's obviously ev pem bro is, is a a very, a very good regimen. We know that less pain, so superior um outcomes and so on. But yeah, so it was not expected. So uh uh not unexpected. So uh yeah, this is an active regimen. We know that the out outstanding results in terms of survival. Um Yeah, so yeah, it's OK. Right. So this, this presentation then in, in terms of, of the, of the SG so that, that you mentioned. So yeah, this poster from Memorial um with overall response rate of only 11%. Um it, it's a bit surprising, right? So, um and I think that patient selection in this uh retrospective analysis matters. So I remember when uh uh Sweeney here uh presented the, the results of permeate in second line, he reported response rate of 26%. And then memorial also reported 0% of PP Merica uh in second line. So meaning that this type of retrospective analysis have limited um like value. Uh We know that c that, that one of the most important things that happened at this as co is the day before as co that the tropics four, the randomized phase three trial uh was uh was uh yeah, it was a press release showing that the primary end point was not met and there was uh uh increased toxic deaths that then in, in as o there was this the sure uh trial that was an IAN trial telling us the same. So that, that likely you need to use G CS F. And now they like uh um tell us all the investigators as just to use proactively, the G CS F in patients receiving SG. So SG is still is a very important drug for bladder cancer. So, um we'll see likely that's going to find out the way just to keep this drug for us in terms of what you have been discussing the cr rates in the, in the CCM Nevo trial. So we need to remember that the lymph node um disease is uh initially is a, is a good prognostic factor for whatever treatment you are giving. So even patients with the long term survivors are those ones receiving chemotherapy only. So, um and then it's, yeah, it's, it's really exciting to see that, that they are doubling the, the the the rate of of complete responses and the benefit seems to be like prolonged, similar analysis was done in the Javelin 100 trial. So, and everybody is doing uh looking in this niche I I was in, in fact, presenting this poster and you see that these patients with lymph node only uh they have a very, very good outcomes. So uh like we will need to that this will never be done a randomized trial um versus a chemotherapy in this uh like a good prognostic uh uh patient. So, and then finally, I think that this, this last um presentation on trans tus map D and so there are a lot of uh of unknowns. Um So FDA has approved a trans map in uh only IHC three plus, but then sometimes you don't know what to do um in mutated patients with uh her two right? That is approving lung cancer, but not in bladder cancer And then um there is a lot of discord between the mutations, for example. And the immunochemistry, I have a patient that has a mutation on, on, on her too. And then the immuno chemistry came negative. And uh and then you have presented this uh this destiny trial showing that even patients with IHC two plus there is a 35% response rate. So, so um and this is not FDA approved. So what we need to do but ask for compassionate use of uh of the exception orders for uh this uh trans map the risk. And I think it's it's new um uh like drug that uh our patients are are going to benefit um side effects. I have experienced that these, these patients have some nausea and vomiting. I don't know if anyone has more experience is not seen in, in, in uh in breast cancer, but in bladder there is a lot of G I toxicity that we like we need to monitor. So, yeah, excellent summary of.
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