Chapters Transcript Video 2022 GU ASCO Bladder Cancer Highlights Back to Symposium Bladder Cancer Highlights featuring Guru Sonpavde, MD Welcome. Thanks for sending the geo oncology conference highlights focused on Ask Ogu 2022. We are going to switch to bladder cancer and I am going to quickly share dr Sampath days disclosures and then um guru will let you share screen to share your slides. Thanks jake. Can you all see the slide set? Yes we can. Okay good. So this is the bladder cancer update and I'm gonna zip through a lot of slides really quickly and I might zip past some of the background slides for the trial since you most of you know all the background for these studies. So as you all know your othello carcinoma treatment has been transformed by a number of new agents. We routinely use the javelin paradigm platinum based chemo followed by maintenance available. And then we have a couple of antibody drug congregates and for the mob and society as a mob. And then we have a targeted agent for FGFR. two or 3 activated patients with the activating mutations or fusions. And in the preoperative setting of course we have the arrival of a juvenile bullet bob in patients with high risk muscle invasive disease, post hysterectomy on a friday trek to me. So getting to the major studies, I will just ah summarize overall to say that there is not something that immediately changes practice but but there was um interesting data that informs us regarding for the development of drugs. So this is the phase three trial that was at D. U. S. Co. And this is a combination of land back with embolism compared with embolism ab alone as first line therapy. So this is the first line trial in patients who were either CISplatin ineligible PDF one high or were platinum ineligible in the first line setting comparing Land Pembroke versus placebo. Damn bro. In the background is just briefly that Jeff and PD one combinations have looked interesting in various phase 12 trials that led to this phase three trials. Now the bottom line is that the data Safety monitoring committees closed the trial before full accrual. The full crew was 694 patients but they stopped Around 2/3 of the way. So why did this happen? Just to looking at this study, you see that this is a bad patient population. First line platinum ineligible patients, Most of them a lot of them have PS 2 80% PS two patients liver, March 25% did not stick out too much for me but it is a bad patient population with the 80% PS two. I've never seen such a high P. S. To patient population in any trial. So the PFS is similar around 4 to 4.5 months median survival similar around one year for both the pem bro and Land Pembroke arms response rate also similar, which I was very surprised you would expect to see some improvement in response rate adding a little bit Response rates similar around 30% for both the arms toxicities of course were more with land pembroke as you might expect, combining a F K. K. I. With temporal map compared to pembroke alone. So this is essentially a disappointing study. Phase three study of a novel combination in the first time setting, But the study may have been compromised by a very high percentage of PS two patients which was 80% of all patients. I will add here that there of course is a switch maintenance trial going on. Looking at a different version of enabled a caboose antonin combined with a violent mob in the switch maintenance during that just activated through the cooperative groups. The second study I wanted to highlight is a Um what the urologist called the 50s to 3 trial. I wonder why How this is a Phase three child. But because this was not randomized in any case this is a study that looked at And I'll 15 agonist called N803 in combination with BCG in BCG. Unresponsive, non muscle invasive bladder cancer. So this drug essentially N803 is an L 15 super agonist. So essentially it activates the innate memory and very NK cell targeting therapy. There was Phase one data looking very promising. So nine out of nine patients had a clinical cr In an early phase 1 30 of nine patients. So this led to this larger study. So this is a study that was done in two cohorts basically the cohort, a carcinoma insitu similar to the group in which Pemba realism eB Ivp embolism OB is approved in a BCG unresponsive disease for C. I. S. So it's a similar BCG unresponsive Ci s cohort and cohort B. Is a papillary disease cohort that is also BCG unresponsive but did not have sis. So the primary endpoint in the cis group for cr at three or six months. Whereas in the second papillary cohort, the non ci escort which was, it was disease free survival at 12 months. So as you can see this is not a randomized study, 88 patients in the C. I. S. Group, 77 in the papillary non ci S group. They were heavily pre exposed to a BCG in the past. So at the uh looks like a slide is missing for some reason. But So the cr rate was 71%. And if you see the C. R. A. At 12 months and 24 months, you see that the duration of Cr was good to the median duration of Cr was two years And the cr rate was 71%. There was efficacy across all groups in this sys cohort and the disease free survival rate is really good because the median DFS is very long. Now this is the popular regroup and similarly in the popular group you see a similar high good outcomes with the disease free survival rate at 12 months of 57%. Which is clearly more than the 20% bar for the lower boundary of the 95% ci that these trials have targeted. So both in the C. I. S. Group and in the popular group there is impressive outcomes. The durability of 24 months. Disease Free Survival. In the popular group, efficacy was seen across all the groups regardless of age and gender and other characteristics of the tur the toxicity rates were quite tolerable. This is an introvert physical therapy, this is not a systemic therapy. Um One of the things that a lot of the urologist I spoke to were um surprised by is this very low grade three event rate. Usually they would expect more D. Syria grade three. Uh and him a jury a not so low like under 1%. That was a little surprising to some of the urologists. But overall the high cr rate 71% cr rate in the cost of my insider group and the long duration of response with the median duration of response of two years was very impressive in the CS group and also in the non ci. S group. So the investigators made a case that given the high cr rate in the cis group Uh with a very durable uh duration of response. And if you look at just the overall denominator of patients around a third of patients maintain cr at 18 months which is clearly higher than what we have seen. Looking across different studies. Looking at the petrol is a map study for instance this was not this high. So As you know with federalism map there was out on the 20% durable cr rate that maintains cr Continuously up to one year. So 20-25%. So it was in the low 20% range and in the papillary disease group. Again they saw a good response good disease free survival rate. So the investigators argued that this is an active drug and based on this data in this non randomized study in a stringent population. But after this drug needs to be made available and I think that the company will go to the FDA probably with these data. So coming to the third study, this is a phase one B study that looked at Travis's map direct again combined with naval mob in patients with her two expressing urethral carcinoma. And this is in post platinum patients with her two high two plus three plus by I. H. C. And they also had a cohort four of her too low patients. But the cohort four did not accrue well only four patients. So really we're going to focus on this. Her 22 plus and three plus patients who received the test is a director can combined with a llama in both platinum patients with progressive disease. So it's a fairly typical patient population. So the efficacy was seen. So 36.6 point 7% of patients had response in this high two plus three plus group especially in the herd to three plus group. The responses were even more frequent. Five out of eight patients. So that's crossing 60% response rate in this high THC expressing group. In the low I. HC. Group there were only four patients but all of those for patients to have a pr. So that's interesting because in this group in the low I. Etc. Group we don't expect um her two targeting to have a lot of activity. But this might be a drug that does have activity even in lower her to patients because of the release of the toxin in the micro environment because of the sizable linker. Of course this is a study done in combination with the volume app. So you really cannot make any conclusions on this small lower her to group. So lots of tumor regressions were seen and toxicities were tolerable as expected. There was some interstitial lung disease seen. This has been seen with criticism of direct stickin but this was manageable and consistent with what's been reported before. There was one patient with LV dysfunction. Again targeting her two can cause LV dysfunction as we all know but seemed very tolerable, very infrequent for this toxicity. So there was some exploratory analysis which suggested that PD L. One cps more than one or more might increase the enriched patients for responding to this combination. And also maybe in the blood based high TMB group, there might be um increased chances of response. So this trust is matt dexter can clearly is a drug that needs further evaluation and study goes on in other cohorts and we need to wait and see where this goes from here. In terms of further development. In a larger story, perhaps randomized study, we're going to the next study. This is the Bayou study. There were a couple of studies that looked at part inhibitors in metastatic urethral carcinoma. So this one the Bayou study looked at first line the volume ab alone or combined with the whole operation in ah in all comers. So we all know that there are patients with DNA damage repair alterations. Um In the tur sometimes you can have germline alterations in these patients which we have shown. So the Bayou study design is quite simply in the first line setting, platinum ineligible or CISplatin ineligible randomized to placebo or Darva will operate. And this was an all commerce study. They did not select patients for these DNA damage repair alterations. PFS was the endpoint Around 75 patients per arm. So around 20% of patients had HR are homologous recombination recommendation repair defects alterations, which is what is expected. And these were the alterations and these were identified based on the foundation assets. So, coming to the PFS in the intention to treat group that the overall group, there was not a statistical difference. When you look at all comers around the four months median PFS. However, when you look at the homologous recombination repair altered group, which was a small subgroup if you know this year. Um Less than 20 patients per arm. There was a significant difference in median PFS going from 1.8 months to 5.6 months and this was statistically significant When you look at overall survival in the intention to treat overall group again, no difference. But when you look at it by the HR are alterations again, there are trends. This study is not big enough to be powered for survival which was a secondary endpoint. But you see some trends here. And one of the interesting findings was that in patients with the H. R. R. Alteration ah they might have the have bad outcomes. It might be a poor prognostic factor because these patients getting their volume alone. You see here had the lowest survival among all of these groups. There was anti tumor activity as you can expect with the development. But you see the highest response rate, 35% is in the group that received their volume map plus in the HR are altered group and if you notice here, their volume alone with the placebo, of course no one responded when they had the HR alterations. So this is interesting data suggests that this combination could have some scope in the HR are altered, a selected group. The safety profile was consistent with what is expected with the whole operation and development, I did not see anything unexpected here. Some G. I. Effects from the development from the boulevard and some of the development of adverse events, some fatigue, so nothing unusual. So um so this combination looks interesting. So the dilemma plus all about it might warrant further evaluation in patients with somatic or Germline H. R. R alterations. A second study that looked at apartment building. This was in the switch maintenance setting following platinum based chemotherapy is the Atlantis study that looked at through cooperative. This is a study in which patients were stable or responding post platinum to some of the javelin situation patients are run are assigned to a group based on a biomarker. And so there's a drd group, there's an air bio market group. There is other no biomarkers positive group. So in the Drd by the market positive group, patients receive or placebo. So actually there is randomization within each of these groups that the patients are assigned to. So this is the group compared with placebo in patients who had these DNA repair defects. It's a small study, Only 20 patients per arm. And the primary endpoint is DFF. So the interesting finding was that PFS did appear to show some difference, I say appear because the p value actually did not meet significance was 0.7 but the trends are clearly quite encouraging for improvement in PFS withdrew cooperate compared to placebo in the switch maintenance setting. If the patient had a DNA damage repair defect in the overall survival, again, the study is not uh powered for survival but there was really not a difference found here. No unusual safety issues, recoverable is overall a tolerable part inhibitor with the routine toxicity seen with some G. I. And some nausea, some fatigue. So to conclude the investigators believed and I agree that there is some scope for looking at apartments villa in this case Rock opera in the switch maintenance setting following platinum based chemotherapy with stable or responding disease. If the patients have genomic alteration in a DNA damage repair defect repair gene and one of the things I'll point out is that the switch maintenance setting might be actually more ah conducive to this design because when you're waiting for genomic testing in the first line setting, it would be hard to wait many weeks for the results to come back while in the switch maintenance sitting, you probably have had time to do them do these essays. Um Send your team out for genomic profiling while you're giving the platinum. So this actually might be a better space to develop a genomic lee guided treatment. Next I'm going to the trophy. You're one trial which is um a trial that looked at patients who are in this cohort which I will focus on. There are many cohorts in the study but in this cohort, patients receive society's map plus petrol is um um if they were progressing on platinum based chemotherapy this is of course Uh instigated by previous data. Looking at promising which showed promising data for combination and photo map embolism map in the first line setting, 73% response rate. And also to appoint somebody is one inhibition does have some immunogenicity as shown in preclinical models. And of course as you know, sausages map is uh approved in the post platinum and pd one study. So in this study, how good was a citizen map Combined with pembroke 34% response rate In just over 40 patients. So there are some patients with durable responses. One of the things that the investigators did want to point out and I don't have the slide here is that a lot of the patients in this study had progressed on platinum and had and had not responded to prior platinum. Only 10% of patients who received prior platinum had responded. So there might be some selection issues that led to the somewhat low response rate. When you compare across studies with the E. V. Pembroke study toxicities were what you would expect with sausages. A map plus temporal is a map. Nothing unusual here with the D. I toxicities and some milo suppression. So this data needs to be looked at in context because there are other trials going on. Evie Pembroke has graduated to the first line space where the Phase three studies going on. So does this data make you want to look at society is a map pem bro in the first line. Probably not yet because of the somewhat disappointing response rate in my opinion in this study. And also because we are waiting for results from this Evie Pembroke first line study. So separatism was being looked at in other trials in combination with other drugs, other immune checkpoint inhibitors. We have one we're going to open here. In fact the people in the world plus hostages map um I I. T. That we have with Moffitt and there is also a study we have here combining society is a map Within 4 to map that we have here the dad trial with brad and I are leading. So we're very excited about that combination. So too I finished my concluding statements on this sassy plus tomorrow study, I think the response rate was lower than expected. Um you can spin it any way you want and say that this is a small study but I think 34% is not a lot higher than what we've seen with sausages. Um um in the third line post platinum and palladium setting. So maybe this drug does not play as well with immune checkpoint inhibition because of my list suppression or immune suppression and maybe there is a better optimal partner. But at the end of the day, maybe we need a better biomarker and maybe we need just we need we just need more data. Perhaps. Maybe there was some patient selection issues in this trial. The last three is the new agreement and for the mastery in muscle invasive bladder cancer, CISplatin ineligible patients. This is core to edge of the V one of 3 study Only 22 patients. Um So one thing I wanted to highlight um which I had the opportunity to discuss at G. U. S. Co was that there were a ton of clinical T. Two and zero patients, two thirds of patients T. Two and zero. And there were also a ton of patients who was just flattened ineligible Just because of hearing loss. More than 40% which is a little unusual. But this is of course a small study. Now the proportion of patients with clinical T. Two and zero can make an impact on Patsy are because we know that clinical T. Two and zero disease does lead to a higher fact cR rate whether you give em back or artist Eliza map in different studies when you look at it clinical stated baseline does matter. So you can stack your trial full of clinical T to patients and achieve a high path cr so that's something to look at when you when you assess non venomous face to new agreement studies. So the path cr rate was 36.4 which is of course quite decent in a small tree with info to map alone. No immune checkpoint inhibitors dr streets were consistent with what's being seen with in format. I don't have a slide here but some Urologists pointed out that there were three post operative deaths out of 22 patients. But I think that this is a small study and unlikely that then photograph had something to do with that. Um But Especially because the TV Pembroke study, the Phase three study is already ongoing and nobody has stopped it early because of some excessive toxicity. So these are the Phase three trials going on looking at various new management regiments and the exciting one is the E. V. Plus liberalism and there are also other chemo plus io combinations in the CISplatin eligible space. So overall E. V. Activity doesn't have activity in the new management space. The paths the rate is impressive. But does the Patsy a translate to long term improved outcomes like disease free survival and overall survival. So we need to wait for that. Um And also when we look at new argument Phase two trials, we should always look at whether how many patients had the clinical T. Two or T three T four disease because that can clearly impact the path CRE and I think we might want to also look at biomarkers to select patients in the new management setting as you know, we have not selected patients based on any biomarker when developing a tv or sassy but in the new adamant space when we're trying to cure more patients, maybe we want more depth of response, improved cure rates, not just improving survival a little bit. So this is something to also look at in the future. Thank you. Thanks guru. Um Fantastic presentation and just kind of a tour de force in 25 minutes of of all the updates and bladder from Shogun. I'll ask one quick question before moving on. Um are there any trials or what one or two trials that that may sort of readout or we may get some results from in the next year. Are you thinking have the most potential to change how we think about treating bladder or advanced bladder cancer? So one of the phase three trials I showed you in the first line setting. Checkmate 901. I did not go have time to go over. It is comparing epidemic nova lima for systems that have been platinum with the co primary endpoints of looking at improved outcomes in CISplatin ineligible And also in the PDF one high Regardless of what platinum patients were qualified for. So that would be one. Checkmate 901. The EV 302 Trial. Evie Pembroke vs Jim Platinum could come out. I'm not sure that we had to look out for that. But more importantly, maybe we will get something from the Phase 2 30, the e. V one or 3 story, which is looking at the E. V. Versus Evie Pembroke o in the first line CISplatin ineligible, which if holds up, you know, validates the response seen in the other Evie Pembroke Phase two study with the 73% response rate. If that holds up, potentially even Pembroke could be approved, but we need to wait and see what happens. Great, thanks so much guru. Published March 16, 2022 Created by
