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 2023.
For those of you just joining today, we're discussing conference highlights from shogun 2023. Um Dr Mantia will be discussing updates in bladder cancer with Dr Joachim Belmont as the discussing doctor man to take it away. Right. Thank you everyone for joining. So today, I just want to discuss a few updates from bladder cancer and G you ask, oh, this year. So there were no big surprises or practice changing presentations, but we had some interesting follow up data from some big trials and then some interesting thought provoking smaller studies. So in the areas to discuss today, so one major study for non muscle invasive bladder cancer, keynote 057. And then for muscle invasive bladder cancer and update on checkmate 274 and a couple of trials looking at different methods of bladder sparing and then in our advanced disease areas, we had a couple updates for some major trials of trophy. You owe one for society as a mob and then in vigor 1 30 for A T cell is a mob plus platinum based chemotherapy. Um And that's not comprehensive. There were a couple of other studies but these are some of the more interesting ones. So the keynote 057 trial was looking at Pemberley Ism and mono therapy for patients with high risk non muscle invasive bladder cancer that were unresponsive to BCG. And so this was looking at cohort too. So we had previously heard from the results of embolism in patients with C I S and the patients with C I S could have had um papillary disease as well. But this is the awaited results from the patients with papillary tumors. So they could have high grade ta or really any T one disease without C I S. The trials that the patients get symbolism of every three weeks for up to two years. And they have disease assessments um at 12 weeks, basically, every 12 weeks, they have systolic api's urine cytology and then every six months they have C T U. And so this showed a 43.5% disease free survival um at 12 months. Um And so this is a little bit better than the data for C I S. Um This seemed to be pretty durable actually. So it dropped off to 35% at 24 months. But then this state study with 35% of patients having disease free survival at three years progression free survival. Um with 88% of patients, you know, being free of any worsening of their grade stage or death from their disease. Um And similarly, for metastatic disease, the treatment related side effects are what we would expect. And so, um overall, about 14% of patients had a serious grade three or four adverse event. You can see them listed here. You know, the majority of the side effects were peratis, hypothyroidism, fatigue. Um but diarrhea was 7% and a percentage of patients with grade 43 to 4, everything else was very rare, under 1% have serious related side effects. And then they also looked at patient quality of life. And so for most patients, their quality of life was stable while they were on treatment, about 20% of patients had an improvement of quality of life and 30% had a reduction. And so overall, this stayed pretty steady while they were on federalism out. So next looking at muscle invasive bladder cancer, we had an update of checkmate 274. So this is our adjuvant study of New Ebola Magnet Boulevard is currently approved in this studying. We are awaiting overall survival results. Unfortunately, we don't have those still. We learned that it's gonna be awhile until we see those as its event driven. Um but we do at least have an update um at 36 months. So we see an ongoing disease free survival benefit with NovoLOG mob versus placebo in the intention to treat population. And so this is a hazard ratio of 360.71. And then this is more impressive in patients with PD L one greater than 1% with a hazard ratio 10.52. And so at least this data is reassuring that the Kurds have stayed separated and we see some ongoing benefit to a juvenile Ebola map. They showed also the subgroup analysis for the I T T population. I think the things to look at of note is that we don't have a lot of patients with upper track malignancies. And so here for renal pelvis and ureter, there's just very few patients. And so you can see the confidence intervals are wide. And so I think what to do in these patients is still a little bit unclear. But keeping in mind, this is a subgroup analysis. Similarly for PD L one, less than 1% still favors no bola mob just barely crosses one. Um But obviously, in our patients with PD L one high, a very good benefit there. They also showed um what's called PFS two or time from randomization to disease progression on subsequent therapy. Um And so this was also improved with noble amount versus placebo. So the next study to talk about are a couple of studies looking at different ways of trying to do bladder preservation. And so this first study is H C R N G U 16 to 57. This was presented by Matt Gorski. And so this is a phase two trial of combining gem cis with Ebola mob and then doing selective bladder sparing in patients with muscle invasive disease. And so the way they did this study was patients got four cycles of gems isn Ebola mad. And then they had clinical restaging. This included a Sista Skopje with biopsies and they had template biopsies, urine cytology and an M R I for patients who are felt to be in a clinical cr they could then decide whether or not to go on active sort of a surveillance where they didn't have surgery or radiation. But they did have no Ebola mob for eight cycles. Or they could choose to go to suspect a me for patients who didn't have a cr they should go right to suspect to me. They had to co primary endpoints in the study. So one was the rate of complete response and then to was how did their clinical cr assessment perform in predicting treatment benefit? And they defined that as either being two years metastasis free if the patients didn't choose mastectomy or if they had an immediate suspect to me having a path cr and so to put this in a little bit of context of the historical cr rate after neo adjuvant chemo is around 30 to 40%. And so in this trial, they saw a clinical cr rate of 43% of the 72 patients who underwent the treatment and restaging. They had 33 who were found to be in cr and 39 who weren't of the patients who had cr 32 of them chose not to have a suspect to me and to go on to Nicola Mob and one had a suspect to me Of the patients who didn't have a CR. 34 went forward with mastectomy and five patients were off protocol. So this is showing the patients that were on Ebola mob and did not have a cyst ectomy upfront. These are the patients who had a clinical cr so of those patients, the 33, were found to have bladder intact metastasis, free survival. And then you can see the patients that record here. So really, there were only two patients who developed metastatic disease and one of those had a local recurrence and suspected me first. And so this is their 30 month bladder intact metastasis, free survival that you can see. So this is their metastasis free survival, landmark analysis and overall survival. So they found that their clinical cr did predict treatment benefits. So again, that was either having two years metastases free if you didn't have a cyst ectomy or having path cr and assist ectomy. So they had a positive predictive value of um .96. They also looked at various markers to see if anything correlated with treatment benefit. Um And they didn't see any correlations other than high TMB. So TMB greater than 10 correlated with flatter and tack metastasis, free survival. And that's likely due to the addition of NovoLOG with the chemotherapy and then um as treatment ongoing. The next study looking at bladder preservation is very different. So this is the retained trial presented by Daniel Guys, Goin Isman um at Fox Chase. And so this study is different in that they are both mutation driven um and then sort of more liberal in the act of surveillance. And so patients um all received em back treatment and how to repeat to you R B T. Um They defined patients who were mutation positive as having alterations, really any alterations in A T M R V. One think see or two, if patients were thought to be in a clinical cr and mutation positive, they went on to active surveillance. If patients had anything less than muscle invasive disease, they could make a choice of inter vestibule treatment, chemo RT or SAS TEC to me. Um And again, muscle invasive disease, they could choose radiation or systemic to me. Um And T three or greater disease. They went on to say mastectomy. So of their patients, um they had 37 who were mutation negative and most of those patients went on to suspect to me. But again, due to kind of their liberal choices, some patients went on to radiation. Um DCG and some patients chose active surveillance Of the patients who were mutation negative and had mastectomy. 15% how to pass cr rate. About 30% of patients had less than muscle invasive disease. 23% had no positive disease. That's mastectomy. 33% of 33 patients had mutation positive. Um and 25 of those were in a cr and so all of those patients went on to active surveillance. A patient who wasn't in a clinical cr also chose active surveillance. And then 33 patients with mutation positive went on to say mastectomy upfront. So one of their endpoints metastasis free survival. So um in blue, you see the active surveillance patients, they had a 76.9%, month metastasis free survival in patients who were not on active surveillance had a 70% metastasis free survival of the patients on active surveillance. 38% of them developed metastatic disease and the patient's not on surveillance. 32 developed metastatic disease. So they did not reach their primary endpoint, they just missed it but they're 24 month metastases free survival. The lower bound of the confidence interval was 62 and that had to be greater than 64%. Um and so they could not say that this approach was non inferior to our current approach. Um They also had a high rate of recurrence to note 70% of patients that were on active surveillance had some sort of recurrence. Eight of those had a mastectomy and then some of the patients chose other options such as chemo R T And only 46% of the patients on active surveillance where metastases free with an intact bladder. I think one of the big problems with the study are that the patients, even when they had a recurrence often didn't have suspect a me. And so you can see that eight out of 10 patients who developed metastatic disease actually had localized recurrence first. Um And so you can sort of see that some of those patients then didn't have suspect amis or had delayed suspect amis or then developed metastatic disease. Um He had presented just a brief comparison between the studies. I think they're very different studies. And so I think it's very hard to compare. Um you know, the HCR N trial used Ebola mob um and actually used an M R I to determine clinical cr which I think is important when you're trying to determine response. Um C T is oftentimes not very reliable in these patients. Um And so the HCR N trial had 70% of patients flatter intact and alive without metastatic disease compared to 46% with the retain trial. There was a very high rate of developing metastatic disease, 38% and retain versus only 6% in H E R N. So some things to consider as we try to focus on trying to help patients keep their bladders, also minimizing patients failing with metastatic disease. So moving on to advanced disease, just two trials to present out of a few that were presented at Asco so one with trophy you owe one. So this is our phase two study of Massachusetts Beauty. Can we're still awaiting results from the phase three ongoing trial. We had previously heard about cohort, Which is patients who progressed after platinum and checkpoint based therapies. We now at the US who heard about cohort too. So this is 40 patients with metastatic epithelial who progressed after checkpoint inhibitor therapy and they were not platinum eligible at the start of therapy. And so we saw an objective response rate of 32% in these patients. And if you took out the patients who also had prior in fort and then the objective response rate was up to 53%. Um and the duration of response 5.6 months um in this objective response rate, especially similar across all subgroup analysis, The clinical benefit rate was 42% when you took into consideration stable disease over six months. And so lastly, for bladder just briefly discussing an update of in vigor 1 30. And so this is a chisel is a math in combination with platinum jumps, I mean versus platinum jumps, I mean placebo for first line treatment of metastatic disease. And so this is arms A and C, we saw as an update here That the overall survival results were just barely not significant. Um so we had for AT cell is a map platinum jumpsuit to being 16 months versus 13.4 without the added realism app. Um and so this was a hazard ratio of .85 and they just missed the bounds for significance. When they looked at patients who received this flatten instead of carbon Platten, there was a bit more of a benefit, but again, didn't reach significance where there was really no benefit at all for patients receiving carbon plan. And so just to summarize, we had a few trials that kind of reassured what we're doing now as standard of care and then some interesting new data. So specifically for non muscle invasive bladder cancer, 35% disease free survival at 36 months for patients with high risk, non muscle invasive disease for patients with muscle invasive disease, reassuring data that the progression free survival benefit That was maintained at 36 months. And then some interesting data on ways to try to preserve the bladder in patients and try to establish what patients are responding. And then for advanced disease, some data for moving this up in earlier lines of therapy with increased response rates and then chemo immunotherapy with materialism and platinum gym cited being not showing an overall survival benefit in the first line. So with that, we can take any questions and I'll invite Dr Joachim Belmont to make any comments of anything that he thought was interesting um of these studies or other studies that you ask. Oh yeah. So I think, yeah, this, this has been an excellent summary of nothing practically changing. Um I would like just only to highlight maybe two points here, the non muscle invasive this we were expecting to see this cohort two. However, the endpoint is completely different from the cohort one that is a C I S where we were looking for A C R at three months. So here the disease free survival um at, At 12 months was the endpoint. And the concern is now that we have more, more approved therapies in that space possibility, likely these results are not going to be uh that useful. So um now that is coming and and other other drugs. So the genocide of industry taxes. So I think it's okay to to know that but it was not really striking data for the human, the checkmate 2 74. We need to mention that this was a three years follow up and we were expecting to see survival results. And as Charlene has mentioned because this is an event driven, maybe we're still going to wait for another year just to see any, any survival data. But 11 thing that is interesting and I compared that study with, with a bigger oh tent that was using a diesel is a map in, we saw that there was a difference in disease free survival. Meanwhile, the patients were receiving immunotherapy and then the curves like uh like crows. Um In this study, we have seen that patients only received one year of the volume up. And despite that the curves are consistently separated, meaning that the benefit is, or suggesting that the benefit is maintained in terms of disease for survival, for the planet preservation, I think. Yeah, interesting. One combination was including immunotherapy. The other not and, and you have, yeah, it's, it's all the time is risky comparing the outcomes. But we see much better results in the ones that we were using immunotherapy than the ones that were mutation driven. Deciding to give these uh em back and, and, and look for broad preservation. I think it's very difficult just to draw conclusions. And then finally, the trophy one, it's, yeah, the data is from a limited number of patients, 32% of responses. And as you have seen when they remove patients receiving chemotherapy that was supposed to be given in the New Testament setting or maybe that I don't know when they received, maybe maybe patients coming from a, I don't know in September likely. So then the response rate is coming up to 53.8%. So it's a bit like uncertain results. So, um and one of the suggestions was to put together this post checkpoint inhibitor with second or third line. So and reach these cohorts and then finally, the bigger again. So confirming the disappointing results of combining in first line chemotherapy and immunotherapy may be one of the, there were two presentations for this indigo 1 30. The second one presented by, by Banias who is the European, they did show the results in patients and feet. Uh for PD L one positivity showing a benefit when compared to chemotherapy and using immunotherapy. The reason is that still has the label in Europe for PD L one positive and they stress that point that there might be still some benefit in this non plan subset analysis. So yeah, if there is any, any comments from the audience. Um I think, Yeah, I think, you know, PDL one positive is this but, you know, I'm surprised that we haven't seen anything in the s even a bit of hazard ratio to make sure we're not over one in checkmate to 74. Well, for the sake of time, we'll move on but Dr Dr Belmont phenomenal discussion, um and with that, we'll wrap up the ladder.
