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 2023.
Welcome to the Asco uh 2023 conference highlights focused on updates in geo oncology. We're gonna start tonight with uh Doctor Mantia discussing updates in bladder cancer. Great, thanks, Jake. Um Welcome everyone. Good evening. So we're gonna start off with updates in bladder cancer. Ok. So let me know if you can't see my screen. It's acting funny on my end, but I think it's ok. So, um we're gonna review a few studies about 2025 minutes to review some of the top presentations from as O in your athel carcinoma. So we're gonna talk about in the locally advanced metastatic setting, the Thor trial of fitness chemotherapy, the no trial of nib or era um and updates to EV 103 cohort a, a four year update and then a couple of per operative trials. So the best for trial looking at Neo AINS is platin based regimens and then the SWOG trial, a surgical trial looking at a lymph node dissection and so forth. First is the Thor study. So this was a study looking at er fit versus chemotherapy in patients with advanced disease with FGFR mutations. Uh the patients had to have at least one prior treatment um with PDL one therapy. Um and then they could have had additional treatments as well. Um And so patients were randomized to fit versus investigate our choice of chemotherapy. Um in the primary end point was overall survival. So, as we would suspect in this patient population, the median age was in the late sixties. Um of these patients, most patients were PDL one, which is what we see in this patient population with FGFR alterations. Um and two thirds to three quarters of patients that had at least two prior lines or two prior lines of systemic treatment. Um And in terms of overall survival, fini was superior to chemotherapy. So, meaning overall survival was 12 months for nib here in blue versus 7.8 months for chemotherapy. So this was a 36% reduction in the risk of death. Um And in terms of progression free survival, there was also a benefit with 5.6 months with artifi versus 2.7 months with chemotherapy. There were no real new safety signals. Um in terms of art fit, it's things that we see in practice. Um high rates of hyperphosphatemia, diarrhea, stroma titi dry mouth, um and the grades of rates of grade three and four adverse events were pretty similar with chemotherapy. 46% and fit 45%. Um similar rates, 8% of patients discontinued fit due to AES and 13% in the chemotherapy arm, there were six treatment related deaths in the chemotherapy group and only one in the group. So, in summary, er significantly prolongs overall survival compared with chemotherapy in previously treated patients with advanced Erel carcinoma with FGFR mutations. The next trial again with er is the Norse study. So this is looking at er um as well as fini plus clia um for patients with advanced Erel carcinoma and again FGFR mutations. Um and so this was actually an upfront study in patients who are splat and ineligible. Um and they were randomized again to artifi alone versus pro plus clia. And the um primary end point was objective response. Right. Again, a similar population with a few caveats. So, um patients were a little bit older, average age um of 72 and they allowed eog performance status of two. And so about a quarter to a third of patients were actually eog two. So a little bit of a thicker patient population. Um And again, we see a small amount of patients who are PDL one high, most of these patients are PDL one low as they would expect. Um And this showed an objective response rate with nib alone of 44% with one cr out of the 43 patients. And for the combination, the response rate of around 55% with six CRS. And so this response rate of 44% is consistent with other studies that we see with fit, um you know, the combination response rate was slightly higher. These are sort of small patient numbers. Um It's difficult to tell if there's much being added with the combination there. Um The interesting part was the duration of response. And so if I the amount the median duration of response was not reached yet, um and as we'll see, there were some, some long durable responses. So this is giving us a waterfall clock here of the responses and, you know, in both groups, um patients had significant tumor reductions and you can see up top um in green uh FDFR fusions and in purple mutations. Um And so you saw responses really regardless of whether it was a mutation or a fusion. And then you can see an orange and high PDL one patients. Um and again, responses were seen sort of regardless of PDO one status as well. And so you're looking at the spider plot um with nib alone with some durable um stable disease and responses. And then here looking at her fini plus the tria again, some deeper responses and then some that were quite durable. Um And ongoing. And so, um currently in the study, there's 25% of patients that um are ongoing on treatment with artifi and 36% in the combination arm. Um This is looking again at overall survival. So meeting overall survival of 20 months for the combination and 16 months for a fit of alone and progression Preser Vival of 5.6 months for a fit and 11 months for the combination. The safety profile was pretty similar. There's not a lot of overlapping toxicity between the two. Interestingly, I don't see rash on here, but again, hyperphosphatemia, uh stoma titi, dry mouth, um dry skin and about 13% of patients um discontinued Salima, 20% discontinued or fit. Um and 14% in the monotherapy arm. There was one treatment related to death due to respiratory failure, which was thought to be related to the immunotherapy clima. So in summary, fit and uh both the combination artifi plus crib had significant activity and first lines of and ineligible patients. Um This is really a small study and it's hard to know how much the crema adds to the combination. And so I think further study studies are really warranted in this space. So next, we're gonna look at the study ev 103. This was a four year update of cohort A um which is the combination of EV plus presa and first line of and ineligible er athel carcinoma. So as a reminder, there's many cohorts of this study. These are patients who are locally advanced or metastatic disease. Um This is cohort A which is the expansion phase of their phase one trial of EV plus pembroke. Um And first line is and ineligible. We also had an update of cohort of K which was a poster presentation of EV. And so um after four years of follow up or EV plus pembroke, um 40% of patients remain on study um which is amazing. So 100% of patients had discontinued treatment, but 40% continued to be followed on study. And so the me and duration of treatment was seven months. And so that was a median of nine cycles of ev uh most patients discontinued due to progressive disease, but about a third of patients stopped due to AES or 20% were patient decision. Um So about 48% about half of the patients had died. Um but there were many still ongoing um on the study. So again, it confirmed a 73% response rate and an 84% disease control rate. So this was the first time that we saw blind independent central review of scans and it was um very concordant with investigator review of scans or 95% importance rate. Um And so the responses were very durable. So looking at median duration of response, it was 22 months, which is really impressive for this patient population. Um So at six months, 74% of patients were without any progression or and were still alive. At 12 months, 64% of patients were alive and without any progression. And at two years, 47% of patients were alive without progression, which is great. Um So 41% progression free survival at 24 months and overall survival in the trial is exceeding two years, um which is great. So 26 month median overall survival and again, you can see 95% of patients were alive at six months. Um 83% in a year and 56% at 24 months in terms of treatment related adverse events. Um, over here on the right are the serious or grade three adverse events. So the most common was um line piece increase which for uh investigators was not clinically significant. Um So the most significant issue we've run into with EV plus pembroke is rash. And so there was 11% grade three rash. Beyond that, it's a lot of fatigue, uh neutropenia anemia, hyperglycemia and then for more mild side effects, of course, uh neuropathy being the most significant, there was one patient death from multi organ dysfunction syndrome. Um and that patient had bolu dermatitis. So in summary, ev Poro continues to show um very high objective response rates, duration of response and immediate overall survival of over two years in the first line to spot an ineligible population. So a couple more studies um left in the preoperative space. So first we'll look at the best for trial. Um And so to remind everyone, this is a study, it's a randomized phase three trial of dose dense MVA or gine cystine as per operative chemotherapy for muscle invasive bladder cancer. This trial has been previously reported but there is some updates um mainly presenting overall survival uh at a. So this in this study, this was perioperative. It can be neo ain or a um patients were randomized to geno plus in four cycles. So this is given every three weeks, um do um six cycles every two weeks. And so they chose this so that um both cohorts would have the same um duration of chemotherapy of 12 weeks. But obviously, when somebody gets six cycles of dose, send them back, there's gonna be more um supply given in that setting. Um As we were doing clinical practice, the patients who got those stents and back did get G CS support during the study. And so this is um their table one from their previously reported study. Um Just a note, the average age of patients in the study is 63. Um and the oldest patients in the study were 69. And so um of the patients who were on trial, um 60% of the patients who were randomized to doin back completed six cycles. Um And then 90% of patients were able to undergo um radical cystectomy. Um The investigators didn't know that there were issues with, with esten anemia and G I side effects with Justin. They thought that um it was still very feasible to give in practice. Um And you can see uh in this graph here, the graph A on the left is Adam chemotherapy. That was a small group that was 56 patients. Most of the patients in the study, about 450 were um neoadjuvant treated patients. And so in the blue here, you see the amount of patients 66% who completed their four scheduled cycles of gem cys versus 58% who completed their six cycles of dosed and ZAC. And you can see below in the lighter color patients who didn't receive their planned four or six cycles. So a little bit higher for the dose, don't come back again. They were scheduled for six cycles instead of four. And then the yellow around the circle is patients who received cystectomy as scheduled. So that was most of the patients previously reported. Um So their primary end point of the study was progression free survival at three years in the entire population. Um So that includes, you know, adjuvant and adjuvant treated patients. Um And so for that outcome, they actually did not meet their primary end point. So the hazard ratio of 0.77 and the confidence intervals crossed one. So P value of 0.066. Um And so you can see in orange, the distance M back versus GC. Um what they did uh is that they did an interaction test and thought that the schedule of the chemotherapy and neoadjuvant or adjuvant um interacted and they, so then they analyzed both arms separately. And so looking at just neoadjuvant treated patients alone, um they had a clinically significant benefit to dose stones and back over GC with a ha a ratio of 0.7. And so what was new with their presentation at A O was also the overall survival results at five years. And so looking at all patients again, um overall survival was improved 33%. This was uh not clinically significant as it crossed one with a P value of 0.078. But looking at just their new adjument population, there was a clinically significant improvement in overall survival of close to 30% for those stents come back um with a 66% 5 year overall survival compared to 57%. They also looked at de disease specific survival and that was significant in both arms. So all comers um with a hazard ratio of 0.63 and then just in the neoadjuvant population with a hazard ratio of 0.56 that was a 75% disease specific survival compared to 60% at five years. This I think was the most interesting data that they showed um for their study. And so one of the big criticisms of this study is that patients who received dos and got six. And so it's hard to compare those patients clearly get more cyst. And so they showed um overall survival stratified by um the arm and the amount of flat and that patients received. And so in the blue is the dose dense m back arms and in the red is the gems. And so they broke it up into groups, cumulative splatin doses with the darker um lines being higher. And so you can see for dose dense and back the dark blue lines for um five and six cycles with the the light blue line being four cycles pretty similar to um gem citing CIN of four cycles. Clearly, patients who did not get the even four cycles of chemotherapy and the light lines down here did poorly. Um and then patients who received increasing doses of cystine um did better in terms of overall survival. So in summary, um I think we have to remember that the trial overall failed to meet its primary end point of progression free survival at three years in their subsequent analysis of neo Ament treatment, specifically six cycles of dose and did improve progression pre survival and overall survival compared to four cycles of. Um I think our big takeaway from this is cumulative cystine dose um was associated with improved overall survival. And so there's a lot of caveats which we can get into into the discussion of this study and sort of how we can apply this to practice. And so lastly, I just want to review one of um an interesting surgical paper. And so um this was the SWOG trial, which was a phase three trial to evaluate standard versus extended lymph node dissection at the time of radical cystectomy for muscle invasive bladder cancer. It was a really well done study which they got into during the presentation. But patients were um randomized actually during surgery. So the patients, uh the surgery was started and patients were found not to have any T three disease. They were then randomized to standard um, pelvic lymph node dissection versus an extended lymph node dissection. And so um a standard lymph node dissection is external and internal iliac and obor lymph nodes. And so this gets 95% of N one disease. Um An extended lymph node dissection adds in pre april um and distal aorta and IVC nodes. And so it increases the node yield by 34 to 40%. Um But as you can see in their study, looking at the two arms, there was really no difference in disease free survival um at five years. Um the lines are really overlapping. And so there was no benefit to the extended lymph node dissection in terms of overall survival. It was the same, really no difference and it's clearly no benefit here to the extent of blue. No dissection of blue. Interestingly, there was actually um worse morbidity and mortality with extended lymph node dissection. Um So the numbers are small here, but you can see higher rates of sepsis. Um 6% and the extended lymph node dissection um and then increased rates of thromboembolic events, um repeat procedures us D hydration. And so the thirty-day mortality was 1.5 for the standard lymph node dissection compared to um or it was 0.3 for the standard lymph node dissection compared to 2.7 in the extended lymph node dissection. And then the 90 day mortality was 2.4 compared to 6.5. And so the big takeaway from this trial was there was no detectable benefit in disease free survival or overall survival with extended lymph node dissection. Um specifically for patients with um local or locally advanced up to N two disease. And then there was greater morbidity and higher preoperative mortality with extended lymph node dissection. OK, great. So I'll invite uh Doctor Joakim Belmont to make some comments um to help us interpret these studies and apply them to practice. Yeah. No, excellent, excellent summary. Um Yeah. So um I I will invest five minutes just to be short. The first thing is that the to trial, I think this is a practice changing in a likely in countries where the, the EV is not available because as as as I mentioned, the chemotherapy that was compared um mm with was a tax. So it's really level one evidence of survival benefit uh of a of a a definitive versus chemotherapy. Um um But the uh obviously, the chemotherapy that was used to compare was not uh EV or SG but as mentioned in countries where eevsg is not available, likely is an option instead of a toxins on or are being floating. So uh I I was really surprised, I think this this was, this was a light breaking after it was hidden in a, in a isolated presentation and but it's likely the best abstract um um tracking changing in in terms of this uh as mentioned, the countries that were like the EV is not approved. So for the Norse um yeah, it, it was a bit disappointed. This is a very small trial. I I think that this is not, is not going to change anything. It's like uh it was presented updated, it was initially presented at ESMO. Um And uh and uh and Tom Powells presented some difference in responses that have not been confirmed. There are some long term durable responses for eb 103 cohort a four years follow up. It's like confirming the activity of ID in in and in first line and fit patient population, 73% overall response rate. Uh So this 26% median overall survival in unfit patients in first line that is really uh uh amazing. And obviously 11 of the things that I haven't seen uh described is the the toxicity um related to pneumonitis. We have seen a couple of patients developing pneumonitis and it's not reporting this trial long term follow up. And it's something that in the summary of product characteristics. I describe pneumonitis can be a a potential side effect, but it's likely not not that frequent for the best part, the best trial. Um I think this is like a squeezing the data, the data. So this trial was already reported European neurology published in JCO. So some people in Europe was were disappointed of this type of analysis and conclusions that the presenter uh ended up the presentation ended up saying, well, this is a new standard of care. This is practic changing, say well. So the main point was negative in the in the per operative. Obviously, there might be a a selected patient population that might benefit of those back. And I I fully agree for some patients, this might be an option. But the number of cycles given in this trial that are six is not what we usually do and patients with a risk of an imperial function likely is not an option. So likely there might be a uh a good option for selected patients. And then finally, the the shock trial was pretty clear it was confirming uh uh at the results of another trial that was in a in a uh running and, and presented in Europe that extendedly no dissection is uh inducing more toxicity and there is no benefit on doing this like a a high highly morbid procedure. So that's my um five minutes comments on the on the um these abstracts and um yeah, happy if anyone is willing just to provide any additional what, what's the median survival Joachim um from the EV Pembroke study. What did you expect in system and eligible from historical control? With MK eight months? It was, yeah, 988, 8.5, 9 months. So uh with Carbo Jam. So it's like um really, really um surprisingly high in this unfit patient population. Yeah, but I will bet that this is less unfit than the one with MKV. And the MCA patient didn't have anything probably later where here or this patient uh received. I'm sure Jim Carbo later and other things. Yeah. No, this might be a, a Bill Rogers phenomenon, you know, or selecting much better um professionally uh clinical trial patients. That is what I'm I'm saying sometimes for these patients. All right. Well, thank you for doc, Doctor and Doctor Belmont. Fantastic presentation and discussion. Uh.
