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 GU 2024.
Ok, thank you. So for anyone who has joined us late, we are presenting updates from as Ogu. Um So I'm Charlene Manti. I'll be presenting the bladder cancer updates. So after some really exciting um presentations over the past year in bladder cancer, there were not as many for bladder cancer at oogu, but there was one long awaited trial, the ambassador trial. So we'll talk about that. We'll talk about some subgroup analyses that were presented from our pivotal ev 302 trial and then two smaller phase two trials, looking at pembrolizumab cabozantinib and then a novel therapy with um PD one therapy in bladder cancer. So first starting with the ambassador trial, this was presented by Doctor Apollo as a reminder, this is in phase three randomized trial. Um This is for patients with muscle invasive bladder cancer um looking at a year of adjuvant pembrolizumab or observation. So in as in similar other studies, these patients can be either post neoadjuvant therapy with CISplatin and still have T two or greater disease. They also included margin positive disease which was a small amount of the population or they could be spotted in eligible. Um or refusing with T three or greater disease. Their study had dual primary endpoints of disease free survival and overall survival. Um So the study was considered positive if either or of the primary end points um met the target. So this was disease free survival in the intention to treat population or overall survival in the intention to treat population. And then we had secondary endpoints looking at PDL one positive patients. So for this study, the study was really impacted by the results of the checkmate 274 study coming out showing that Nivolumab improved progression free survival, which led to FDA approval for adjuvant Nivolumab. Um Ambassador was still ongoing. At that time, we had, we had this open at Dana Farber enrolling patients. And so the study was um closed a little bit early due to this approval of nivolumab. And so this really impacted the results as we'll see. So overall, they enrolled 702 patients split between pembrolizumab and observation. Some of the patients 24 and four never started treatment. And then as you can see, um some patients moved on to alternative therapy or withdrew from the study altogether. This was 20% in the Nivolumab arm and 33.5% in the um observation arm. Um So in terms of the characteristics of patients for this study, um as we mentioned, patients, you know, could be t two or greater if they received neck or T three or greater if they couldn't receive CISplatin or refused the positive surgical margins. Patients with a really small percentage, 2 to 2.5% of the population, most of the people were T two or greater. Um There was an even split between PDL one positive and negative and then they had about 20 to 22% upper tract patients. They didn't limit the enrollment. This is just what they ended up with. Um and then a fair percentage, 15% of variant histology. So you can see the trial did meet the um disease free survival end point. And so um the disease free survival, median disease free survival for pembrolizumab was 29 months and it was 14 months for observation. So about a 30% reduction um in the risk of of progression or disease recurrence um which met the primary end point. You can see that for the most part, um this was similar whether or not patients received new adjuvant chemo whether or not they were pl one positive or negative age. Um the upper track patients as again, as we've seen in similar studies, you know, crosses one. you know, there's fewer number of these patients. Um And so it's hard to know what to make. And I think we need more studies in upper track patients. What was really interesting to me about this trial was that um PDL one didn't make a difference in that. Um You know, there was no improvement in PDL one positive patients. Um no difference in the improvement with pembrolizumab. But actually, the patients with PDL one negative disease did fare better with pembrolizumab. So PDL one was prognostic in that overall patients with PDL one positive disease did better. Um but then patients who were PDL one negative um had a greater improvement with pli zab compared to observation. So this is in contrast with some previous data we've seen from other studies in bladder cancer. Um And so that's an interesting point. Unfortunately, this trial did not meet the overall survival end point. Um you know, this data is ongoing. Um But at this time, the media overall survival was very similar and you can see that the curves really overlap for Pumba zab um versus the observation arm. Um Similarly, you know, for overall survival, there was not one specific group that really benefited from the pembrolizumab and looking at PDL one, there was really, again, um no difference whether the patients were PDL one positive or negative for overall survival. So, in terms of, you know, how is this trial impacted, you know, by the approval of nivolumab? Well, for patients in the observation arm, um about 22% of the patients had received checkpoint inhibitor um after the disease free survival um end point, you know, and so I think that did play a big role in this study. About 30% of patients did receive alternative systemic therapy. Um And I think that impacted the results and this doesn't include the patients who withdrew consent and dropped out in terms of adverse events. It's exactly like we would expect for pembrolizumab, no new safety signals, a lot that impacted this trial. Um especially with Novoa being approved um in the trial stopping a little bit early. All right. So next, we're looking at EV 302. and so a subgroup analysis was presented at Gasco. So just as a reminder as I'm sure most of you are aware this was such a pivotal trial in ethel carcinoma. Ev 302 is looking at locally advanced or metastatic ethel carcinoma. Um in patients are randomized to either EV PMRI first line or chemotherapy. Um either CISplatin or Carboplatin and gemcitabine. And there were dual primary end points of PFS and OS as a reminder. Um We saw these results recently at ESMO and EV Pemra, you know, reduced the risk of disease progression by 55% and similarly, by greater than 50% improved, um reduce the risk of death. And so median progression free survival was over 12 months in pembroke group versus six months for chemo. Um and median overall survival was estimated to be 31 months with EV Pember and 16 for chemo. So far, the median follow up is only 17 months. And so that may change with time, but it is very exciting and you know, we've previously seen this data. Um no new safety safety signals with the combination of EV and PML. So what's new at gao was looking at the subgroup analysis. And so they showed um the PFS based on susin eligibility, which you can see at the top. So whether patients were SUPA and eligible or ineligible, really the benefit here with the hazard ratio of 0.48 and 0.43 is very similar, excellent improvement in PFS. And then for PDL one high and PDL one low disease, similar improvement in progression free survival. We also looked at whether or not there were liver metastasis present, you know, which is a poor prognostic factor for bladder cancer. Um again, still a very good improvement um in PFS with EV PMRI, same for visceral metastasis and lymph node only disease. So as you can see, this is actually very clear um that the hazard ratio favors Ev Pember for any subgroup that we look at in urothelial carcinoma. And they show the same results for overall survival. And, and the gist of it is that there again is a very a big improvement in overall survival for EV Pembroke. The really regardless of subgroup that you look at. So whether or not patients have poor prognostic factors like liver METS, um low PDL one other subgroups all benefited from EV PMR. And so this is looking at objective response rate for the same subgroups. So you can see patients that have high PDL one with the CPS score greater than are equal to 10, do have a uh you know, slight increase in the um response rate that we see at 70% compared to 63%. But overall, um any subgroup you look at had over 60% response rates of 60 to 77% for lymph node only disease, which is great. So again, conclusions are that, you know, the benefit of VR is very similar regardless of subgroups, the spot and eligibility. Um Visceral metastasis PDL one. So this supports VRL for any, you know, metastatic or locally advanced urothelial carcinoma patient. OK. So two quick um phase two studies. So this is called the PEM cab study. This is looking at cabozantinib plus pembrolizumab as first line therapy for your metastatic or advanced urothelial carcinoma patients who are CISplatin ineligible. And this was presented by doctor J. So these patients had to be CISplatin ineligible or if they were platinum ineligible. Um Their PDL one status didn't matter if they were CISplatin and eligible. They had to have PDL one high CPS greater that are equal to 10%. Um which is, you know, the guidelines that we previously had used for single agent PDL one therapy up front. Um These patients received pembrolizumab every three weeks and daily, 40 mg of cabo. The primary endpoint was objective response rate. Um So these patients actually had a fair amount of upper tract rethel carcinoma, about half upper tract, half bladder, mostly pure ethel at 77%. Um, a small number of lymph node only disease patients. These patients were mostly patients with visceral mets at 78%. Um And about 22% had PDL one high, greater than 10 CPS score. And then because these patients had to be clit and ineligible, um, most of them, about 70% had a reduced creatinine clearance between 3060. Um So, as you can see in this small study, um of about 36 patients, um patients fared pretty well. So 80% of patients had some tumor shrinkage and this was um across any of the CPS low or high scores. Um So this came up with an objective response rate of 45%. There was a 14% cr rate, 31% pr rate in a 25% stable disease. So, really about only 28% of the patients had um progression. This is looking at um individual responses. And so you could see the patients that unfortunately progressed right through, but that was very few. Some patients had very deep and in some cases pretty durable over 30 month responses. Um So median duration of response was about 15 months. Um and eight patients out of the 34 patients or so had ongoing clinical response at the last follow up, which was about 20 months. Um median progression free survival was 7.5 months and overall survival 17 months in terms of treatment and emergent adverse events. Again, what we would expect for cabozantinib um in combination with the checkpoint inhibitor. So mainly um you know, palmar, plantar, erythro dys diarrhea, fatigue pruritis, um nothing out of the ordinary. Um there was a fair amount of immune related toxicity. So 83% of patients did experience immune related adverse events and 11% of patients required high dose steroids. Um patients did make it through about 10 cycles of Pembrey and seven cycles of Kantin. Um So the rate of grade three or greater treatment emerged, adverse events was about 50%. So, in conclusion, this study though, it had a, a fair response rate of 45% didn't meet um the lower bound of their response rate of 32% they would have needed 17 responses and they only had 16. Um And so technically, this study would not move forward. Um The other concern is that there, there was a fair amount of toxicity and so this is a tough regimen to tolerate. Um But I think it's very interesting to look at the results of a Vegf inhibitor with immunotherapy in bladder cancer. And so maybe a more tolerable veg E inhibitor or um you know, biomarkers trying to decide which patients should receive, this could be something to evaluate in the future. Ok. And lastly, um was a study presented by Doctor Gals of oral A pl 1202 in combination with talum as neoadjuvant therapy in patients with muscle invasive bladder cancer. So, this was an interim analysis of a phase two trial that's ongoing. So, a pl 1202 or nitroxylene is a reversible and orally available. Met A P two inhibitor. So it has anti angiogenic and anti tumor properties. Um They combined this with a anti PD one antibody talli. So previously, they had done a phase one study of the combination. And then they moved forward with the RP two D of um 1125 mg of a PL 1202. And so this was now looking at the phase two study. Um group one was the combination of Talab plus a PL 1202 versus group two, just Talab. And the primary endpoint was a pathologic cr rate. So they had 42 patients that were enrolled um during the study, 10 patients ultimately refused to have a cystectomy. And so those patients um were censored as the primary endpoint was path cr and so they had at the end of the day, 32 of valuable patients. So this was 18 in the combination arm and 14 in the monotherapy arm. Most of these patients 60 to 70% were stage two disease. But um a fair amount, about a third to 15% were stage three and some stage four, um about half were PDL went high versus low. So, their pathologic complete response rate was about 40% in the combination group versus 21%. With just the PD one therapy Tillis AAB. They had a 44% downs staging rate. So, less than muscle invasive disease compared to 21% with immunotherapy by itself, this did trigger um an expansion to stage two of their design for the trial. So this will be ongoing. Um They did find that 33% which is, you know, these are small numbers two of the six patients with stage three T three disease did achieve a path cr in the combo and no patients achieved a path cr with just immunotherapy alone. Um The drug itself was pretty safe. There was about 60% of grade three treatment, emergent adverse events. These were typically anemia reduction in white blood cell count. Um and then ferti itself was very tolerable. Um So some low levels um of anemia and decreased blood counts. So, you know, with a path cr rate of about 40% they are planning to do more studies of this combination. I think, you know, this is very early and um I think the data looks ok, you know, not super impressive but something to look forward to seeing more of in the future. Ok. So at this time, I'll turn it over to doctor Belmont for his comments on our bladder cancer studies. Um from Gasco. Yeah, tha thanks Charlene. So um yeah, good summary of. Uh yeah, there were no so exciting studies but yeah, I think the ambassador was the one that we were all looking for the results of this trial. We heard that it was negative. And um obviously, uh we tend to compare this trial with the, with the new volume of a human trial. And there are some differences that are really a bit surprising. So um uh the hazard ratio is uh a bit inferior, the, the data that you have presented about the, the, the, the, the, the PD one expression. So um we know that the volume up in Europe is only approving PDL one positive. So, um and in this trial that the results were completely the other way. So the patients with PDL one negative did better um in the observation arm versus the temper Liza. So yeah, PDOPDL one was a, was a prognostic factor in this trial. Uh But as mentioned, it was a bit surprising that the PDL one negative did benefit in the observation arm more than the paroli ma treated patients. Um Yeah, the hazard ratio was uh 0.69 that we know that in the PDL one with Nevo, it's like uh 0.0 0.53. So it's, it's really uh quite different despite the, as you have mentioned, uh the, the there was a lot of withdrawals in in this trial. So um this one, this trial was the observation is what it was an observation um arm purely it was not a placebo like in the new volume of arm. So based on that and, and the other thing that, that it's surprising is like the survival curve. So we are all a bit like surprised that uh even the for the new volume up trial, we haven't seen any survival benefit despite some data um presented like uh at EU for three years follow up and we saw at this as OGU also a simulation of the potential benefit of the new volume up given in the adjuvant setting about survival. Um But, but meaning that we are not seeing that maybe uh ACU is going to benefit in terms of uh disease for survival but not uh in terms of overall survival. And this is a bit surprising and even some, some people say, well, if we have a good combinations that are rescuing patients early may is not worth it to invest on giving an adjuvant immunotherapy. So that's a, a very, a very bad way just to see these results. But yeah, in fact, now we have uh 22 options. Um and in terms of the adjuvant setting using uh PD one inhibitors and uh the ambassador and he met the, the, the, the endpoint of, of uh DFS. And uh this is a new option for our patients and we'll see uh what FDA is going to do uh for uh for pa Ma in the avant setting. And then I was a bit disappointed about the sub group analysis of EB 302. I was expecting to see more exciting data. So yeah, so the conclusion is, is like as you mentioned, so um any subgroup benefits when uh when, when receiving uh like IBM, bro. Um and uh yeah, nothing new was, was presented here. Uh I was expecting to see more data on uh how to manage long term toxicity with EpiPen, bro. How many cycles patients are able to receive all these questions that we are facing in the daily basis? So, but yeah, we need like we need to see the final publication and hopefully uh more, more uh data will be provided about the uh all these uh type of uh of nuances when giving EpiPen to our patients. And then, yeah, you have presented the, the, the TCO this this trial that again, uh we have been trying to combine um um BGF antiangiogenic with the PD one inhibitors. And we know that the lip trial that was uh combining pembrolizumab with Labatt that we know that it's highly effective in in kidney cancer. So it's not working in bladder cancer. And here again, this combination of pembroke anin in ineligible a bit disappointing despite there were 14% of patients obtaining a complete response, but it, it seems that this is not the best way to go in patients being metastatic. However, you have presented this uh interesting Eva study uh using an an antiangiogenic that is a bit different with the, this PD one, the uh TL Liz map. And uh it's exciting to see this pathological complete responses, 40% down staging in 44%. But we will see um what's uh the future of combining these antiangiogenic and PD one inhibitors in a, in a in bladder cancer in anybody on setting. So I think, yeah, just, just to conclude, ambassador was a, a AAA new, a new uh trial being positive in the anti setting, we know that the, the PDL one inhibitors like the tesol of the invir 0 10 was negative for DFS and uh for OS. And uh obviously the, the the markers might help to identify and this is what we are doing now with the Indigo 0 11, identifying patients with a, with AC T DNA positive to give or not to give it one therapy. So the future uh maybe we'll be moving towards this direction. Right. Thank you very much.
