So, uh that was sort of like the localized portion of the talks. So now we're gonna move on to a more advanced disease, bladder uh prostate and kidneys. So we're gonna start off with Doctor Myron. He was a uh resident at Temple. He was a fellow at Fox Chase. Uh stayed on his faculties, published a lot in bladder cancer, really an expert in CT DNA. So he's gonna update us on bladder cancer and what's been going on. All right, thanks everybody um for your attention in advance. I'm very happy to be able to talk to you today. So I'm gonna talk about the changing landscape um of advanced bladder cancer. And I think I'm fortunate because for many years, this lecture might have been uh less changing than it is now. So, uh this year, we've had a lot of big changes and I have the privilege of talking about them today. So this is how I would have presented kind of the timeline of bladder cancer uh treatment and advanced disease um very recently as of a few months ago. So the first line standard of care for many years has been platinum based chemotherapy as many in the room may know. And I highlighted in 2020 that there was an overall survival benefit shown for maintenance immune checkpoint inhibitors after platinum chemotherapy specifically of vab. And that was a big advance for patients um in the first line setting. And we've had multiple approvals as you can see based on the timeline in other disease settings. But that was a real shift. Uh For first line, we have single agent immune checkpoint inhibitors, an option, first line and also second line. And then in later lines, uh we have antibody drug conjugates and FGFR uh tyrosine kind inhibitors. And if I had to summarize kind of a flow chart of the standard of care for advanced bladder cancer, um this is how I would have done it. So first step determine platinum eligibility. If a patient is eligible for for platinum, the first line of standard of care would platinum based chemotherapy with CISplatin or carboplatin combined with gemcitabine or another uh backbone like M VAC. And then patients who achieve disease control would go to maintenance, immune checkpoint inhibitors. Whereas those who progress would go into immune checkpoint inhibitors as per standard of care uh as a second line regimen. And then after uh that step, um if you have another progression event or intolerance, you go to uh antibody drug conjugates or FGF RT KIS. Um going back to the beginning if your patient's ineligible for, for CISplatin or carboplatin you'd start with an immune checkpoint inhibitor and then move to AD CS or FGF RT KIS. And I have to say that as of emo 2023 time, the clock is up on uh that flow chart. So it has to be a new slide has to be made and uh I haven't done it yet. Um So spoiler alert at the end, I don't have a new flow chart for you because I think there's a lot to process, but I'll go through the data and hopefully um the community can come together and figure out what that is. So the overview for today is just gonna be a summary of three important phase three clinical trials from ESMO uh 2023 just a couple of months ago. Ev 302 being the first study I'm gonna talk about uh checkmate 901 and then Thor uh the thor study specifically cohort two, I'm gonna focus on a little bit. So ev 302 as many may know is an open label randomized phase three study of inform the doin in combination with pembrolizumab versus chemotherapy, specifically platinum based chemotherapy and previously untreated patients with advanced or metastatic uh bladder cancer. The study design um to just kind of quickly highlight the important things to know it is again, previously untreated population, they have to be eligible for platinum based chemotherapy because that was the control arm. Um PD one PDL one naive and um the GFR cut off was 30 or greater and ec og performance status of less than or equal to two. Uh The randomization was 1 to 1, uh 886 patients uh were included in the study randomized to EV Pemra, which is what I'm gonna call it uh for the remainder of the talk and uh or chemotherapy. So, um the chemotherapy control arm was CISplatin or carboplatin combined with the gym Cytopan for a max of six cycles. And the primary end points were PFS and OS with a number of important secondary endpoints as well which we will cover. So, uh the first thing I like to think about when I look at a clinical trial is how much does it represent the patients that we treat and um and how well balanced are the arms. So without going line by line, um take my word for it that the arms were well balanced. And I tried to highlight a couple of things that stood out to me um when thinking about our patients. So the first thing I'm highlighting is the geographic location. And it's important to note that in this study, um only about 20% of patients uh in each arm were recruited from the uni from North America. So United States and Canada and um about 40% from Europe and then rest of the world had a substantial proportion of the study about almost 40% as well, with regards to performance status, I do think it's um fairly well split between E COG uh zero and one. But you'll notice that even though the study criteria did say that you could have E cog performance status of two, there were very, very few people um who had an E COG performance status of two. So those kind of sicker patients that you may see in clinic, not many of them made it onto this study. There were patients with upper tract and lower tract disease and um there was a good split of about 5050 for CISplatin eligible patients. Uh This is uh this the what I wanted to highlight in the next section of of metastatic sites was actually liver metastases. Um An important point there was that this study did include some patients with high risk disease with liver meds. So about 20% in each arm. Um I mistakenly highlighted lug mes, but I mean, it's still important to kind of look at this um metastatic spread. Uh But I think it's important to note that there were some sick patients in this study. So looking at the primary end point first progression free survival, you'll see that the there's a dramatic difference in progression free survival between EV pem bro and chemotherapy with the hazard ratio of 0.45 with tight confidence intervals around that. Um statistically significant with a median of 12.5 versus 6.3 months. Uh You can see that the curves separate and stay apart early. I have separate early and stay apart. I should say looking at overall survival, uh the same is true. So um hazard ratio again, remarkably good 0.47 with tight confidence intervals, statistically significant at an early uh time point. So the the analysis was really meant to look at progression free survival early. Uh But overall survival was significant, obviously here, you can see that and um and it was dramatically improved with EV Pembroke versus chemotherapy. What I think is really remarkable is the median overall survival is really unprecedented in this study for first line bladder cancer with 31.5 months uh for EV pembroke versus 16.1 months for chemotherapy um with a median uh survival follow up of of 17 months. So you can see that this is kind of a wide separation of the overall survival curves that does seem maintained over time. And I think one question that a lot of people had when they were kind of anticipating the data for this study was, what was it gonna look like in patients who were CISplatin eligible? Because we've already had an accelerated approval for EV Pembroke for CISplatin ineligible patients. And we've, you know, many people have been using that in clinic, but there was a question kind of would CISplatin eligibility be a biomarker of some kind with those patients respond differently to ev pem, bro, are they biologically different in a way that would be meaningful? And I think that this subgroup is important and they did show this in the main presentation, you can see that the hazard ratios for, for survival based on CISplatin eligibility were not significantly different in my opinion. Um Their, their benefit was clear in both groups another way to represent overall survival with a forest plot. They didn't break it down into two too many subgroups. So, um overall, I think that leads to narrower confidence bars. Uh But you'll see that all of the subgroups benefited. Um Although it wasn't kind of surgically broken down as some studies do, um You can see that there was a benefit across all the the subgroups listed here for overall survival. And I don't think it's important to focus too, too much on each one individually. Um But you'll see upper tract, lower tract, for example, in the middle um liver metastasis, which I kind of highlighted at the beginning. Uh You'll see the benefit in both of those groups. PDL one and CISplatin eligibility that we already talked about. Um So now looking at some secondary endpoints response rate and duration of response, I think both important things to think about with this regimen. So um not focusing on the overall response rate too much, but looking down towards uh median duration of response, I think, um although we don't have a number for the median duration for EV Pembroke, you'll note that the confidence interval, the lower bound uh is at 20.2. So it's 20.2 to un to not reached. Meaning that that's kind of the lower bound of the estimate, which is pretty remarkable. Um When you look at chemotherapy in comparison, you'll see that the median is only 7.0 that median was reached and you could see the confidence intervals kind of suggesting to you that the best it could be is 10.2. So I think that's a AAA notable difference in the longevity of response that the patients experience. And then I just wanted to highlight um progressive disease as far as overall response rate because we know that disease control is important. You can see that when you compare V pembroke to chemotherapy, that there was pretty good disease control with chemotherapy, you know, ev Pemra was better. But the disease control rate, there were only 13% of patients are, you know, give or take who progressed uh primarily with chemotherapy. So patients do respond, but the longevity is very different subsequent therapy. Um an important thing to consider, especially with international studies. So I think that uh one of the things that I didn't mention in the beginning uh when looking at the study design was that a vab maintenance was not part of the initial study design. Um that was um approved. I think after the study was already launched and there was an amendment made on in during the conduct of the study to allow for development maintenance, but it was relatively late in the, in the study. So I think a lot of people were anticipating and wondering uh what that number was gonna be for development, a maintenance therapy. And so I highlighted it here that it was 30% give or take for the control arm. And I think that's actually pretty good. I was really pleasantly surprised to see that. I thought it could have been much worse given the timing of the amendment. And um I think in a perfect world which doesn't exist in a clinical trial or in clinic, um you could say that maybe the highest it could have been is 50 or 60 but that we know even in clinic that every patient that's eligible doesn't actually get it. So I think 30% is pretty legitimate. Um And then if you go down to others, kind of like the final category for subsequent therapy, I don't think it's fair to kind of throw this out there entirely, but, you know, subsequent ev um probably was not a big factor in this study. I showed that the distribution of patients accrued was kind of uh worldwide. Um It's not a standard uh second line option uh in this such situation, but a lot of clinicians do use it. Um So, you know, well, that's a question mark. A quick look at toxicity. Um So I try to highlight some salient points here. You'll see that there's more significant neuropathy with EV Pembroke as compared to chemotherapy. I think part of that has to do with the fact that chemotherapy is given for a fixed course and then has to be discontinued. Whereas V Pembroke is given for a longer period of time and more patients to develop neuropathy, there's also unique skin toxicity with EV pembroke um represented as pruritus and also maculopapular rash. Uh So that's a unique toxicity with informa and it seems to be a little bit uh exacerbated with the addition of pembrolizumab and then down to the bottom, there's more mild of suppression with platinum based chemotherapy was what we would expect. I think the way I would summarize it uh with the line at the bottom is that Ev pem bro has a significant side effect profile. I think it's kind of marketed as a targeted therapy. But I think the toxicity profile and people who have used it kind of understand that it's not really a targeted therapy. It's more targeted than, than maybe chemotherapy. It does have unique side effects that have to be managed carefully. Um So moving on to checkmate 901, this is nivolumab plus gym cytopan CISplatin versus uh gym cytopan cystatin alone for previously untreated patients with again, advanced or metastatic disease phase three study. This is the study design. Um again, it's fairly similar but there are a few differences. Um So these are again previously untreated patients. Um and it does include upper track patients. All the patients notably had to be CISplatin eligible. Um by definition, because the control arm was a CISplatin based control arm and the performance status was appropriately limited to E COG zero or one you know related to CISplatin eligibility. Um randomization of 1 to 1 300 in each group. And the experimental regimen was Nevo GM SIS for up to six cycles followed by Nevo maintenance strategy versus uh just gem cis for six cycles. And the primary end point were OS PFS. Uh with some key secondaries. Excuse me, again, looking at the baseline characteristics here, I really highlighted one similar thing again, well balanced uh between the two arms. Um You can see that this study really didn't recruit many patients at all from the United States. So thinking about our patients and clinic, there's basically no patients in this study from the United States. Most of them were from Europe, Asia or rest of the world. Um Again, also had about 20% liver metastases in both groups, upper tract and lower tract. And one of the interesting slides I think from the initial presentation of this study was that uh was was kind of on the patient disposition. So just one key kind of observation here, um most of the patients completed six cycles of gem cis Nevo but less patients kind of interestingly completed just GM SIS and you would think that when you add a drug, you would have maybe more toxicity and patients would be completing uh maybe less cycles for different reasons. But, you know, obviously if you're getting less of a response, you could have disease uh progression as a reason for discontinuation of therapy before six cycles. So those are kind of the two things to think about. But when you look at the uh reason for discontinuation of therapy, there's only there was a 20% difference uh between the arms and only 10% was accounted by disease progression, which I thought was a little bit curious, meaning that um you know, there were patients who are discontinuing for toxicity uh at equal rates. So there's something kind of unaccounted for here that I think it's uh bears thinking about um looking at the primary end point of overall survival. You can see that there was a difference between the two curves, the GSIS Nevo on top um hazard ratio here less dramatic 0.78 statistically significant. But you can see that the confidence intervals kind of encroach on one. but the curves do come apart and stay apart, progression free survival. Um again, was also statistically significant with the hazard ratio of 0.72. Um where you can see that the curves kind of do come apart and their list seems to be a little bit more of a longevity of of of progression free survival for jem cis neva. Looking at uh subsequent therapy, I think the real only takeaway for this that I think is worth thinking about is that the overall amount of immunotherapy received in the control arm at any time after was only 40%. So if you think about what I showed you for the other study, there was 30% just maintenance therapy. So for this study, 40% of the patients in the control arm got any immunotherapy. So low rate overall of subsequent immune therapy, this was also designed before maintenance of elim. So that's like not a fair criticism uh but not a huge uptake of immune therapy after progression treatment related AES, there's not really a big highlight here just to say that gem cis neva was well tolerated. I think in comparison to platinum based chemotherapy, there was a slightly higher incidence of grade three toxicity, but I I wouldn't say it's a very significant one and I think overall it's well tolerated compared to the control arm. So when you look at the two studies compared uh ev 302 and and checkmate 901. So checkmate 901 is slightly bigger study of only uh cyst eligible patients. Um EV 302 control arm had a 5050 mix of gem cy and gem carbo. And I think both studies have a similar kind of critique in that um only a fraction of patients were enrolled from the US and there was maybe an arguably suboptimal subsequent therapy because of that putting kind of the end point side by side, which we're never supposed to do. But we have to um if you look at disease control rate, um good for both regimens. If you look at overall response rate, good for both regimens but better for VMRO C. The cr rate is a differentiator for VMRO with 39 in the study versus 22% median duration of response. Again, clear differentiator for EV pem bro, uh not reach versus 9.5 months. So, not too far off from what we saw with the chemotherapy control arm for EV 302 is where checkmate 901 kind of came in at PFS again in favor of EV Pembroke uh with a hazard ratio that's more impressive and a median that's, that's longer. And the same thing is true for overall survival. Now, just a couple quick words about uh the Thor study. So this is another phase three study. Um cohort two, which is the bottom uh piece was, was presented at Emma EMA, but I'm just gonna show a tiny bit of data from both of them. So this is a randomized phase three study, open label with two independent cohorts that were analyzed separately. Again, cohort two was presented more recently. Cohort one was previously presented as Ti Fit Nib versus chemotherapy in patients with FGFR mutations who progressed after one prior treatment including PD one or PDO one cohort two. However, was artit versus pembrolizumab in patients who had advanced disease that had progressed after one prior treatment that was not immune therapy. Um So, you know, it could be chemotherapy, for example, just a quick background. FGFR alterations are are pretty common in bladder cancer. Uh uh you know, the estimation kind of ranges, but in this presentation, they estimated a about 20% which I think is fair because it's one of the bigger studies that kind of looked into that. Um and it is higher, uh there's a higher incidence in upper tract disease and we know that this is a real driver mutation and there is some evidence that suggests that FGFR mutations may be associated with a slightly less immune infiltrated uh tumor. Um but that's not really the main focus of this talk. So cohort one, like I said was previously uh presented um and this was Tiit versus chemotherapy in second line. Um And this chemotherapy was not the same as the chemo we were discussing in the prior studies. This is uh dosa Taxol slash in fluing common chemotherapy used uh in subsequent lines of therapy. And you can see that Tiet nib here had a longer meaning overall survival that was statistically significant and met its primary endpoint um versus chemotherapy and second line. However, cohort two, which was recently presented at emo showed something different. So this was of fit compared to pembrolizumab in second line. And here you could see that over uh of fit did not improve survival versus um pembrolizumab. And you can see that the pembrolizumab curve in green, which is actually coming out on top at the end looks to have a more durable uh survival benefit. So the primary endpoint wasn't met. So I think conclusions um just overall for the, the entirety of the presentation are that uh for me, Ev Pembroke produced unprecedented pfs and OS with an acceptable toxicity profile compared to platinum based chemotherapy. A couple questions is a control on with 38 30% maintenance of ma good enough. Um I think people have to ask themselves that and I think uh um a point that I really wanted to highlight was they didn't in the initial presentation really go into the number of cycles of EV that were given on the study. And uh we don't really know exactly how many cycles of EV you need before you transition to single agent. Pembrolizumab. And uh doctor Kalia who's here has a study looking at a little bit more detail about the dosing schedule for EV Pembroke, which I think is really important and maybe learning from EV 302 and, and, and her study moving forward, um gem sis Nevo did improve PFS and O OS. But I think incrementally uh with accepted added toxicity it was a positive study but it's in the setting of two negative uh phase three studies with uh talli M and Pembrolizumab in a similar population and setting um slightly different. But uh it, it's still worth noting and Ettin is an active drug. We do know that uh it was positive versus chemotherapy. Uh but it does have a challenging, unique side effect profile and um was not able to beat immunotherapy in the second line. So looking ahead, I do think that Ev Pembroke is the new standard of care for F for bladder cancer. In first line, I think a question that comes up is what patient would you still use platinum chemotherapy for in first line? And with that question in mind, is cis platin eligibility still even important in the metastatic setting. Uh Should it be a stratification factor for future trials at all? Uh Given that I think this should be the standard of care for most patients. Um I think there's still a lot left to learn regarding uh sequencing of other approved effective therapies and those that are in development, which is why I'm not gonna show another flow chart. Um We still have chemo uh FGFR inhibitors and other AD CS including Sat Meti, which is already approved and her two AD CS, some of which are approved in summer development. Um And that's it. Thank you.
Related Presenters
