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 ESMO 2024.
Hello, everyone. And for those who are just joining us, this is our Geo Oncology emo conference highlights. And for this part of the uh program, we're gonna be discussing the bladder cancer updates. My name is Vincent Xu from Dana Farber Cancer Institute and I'll be joined for this section by Doctor Joakim Belmont will be our discussant looking at bladder cancer. At a glance, we have one. I would argue revolutionary practice changing trial which is peri operative Derval in combination with neoadjuvant gem cyst, which is the new standard of care in cyst eligible muscle invasive bladder cancer. And we have updates on new options for both localized and metastatic ero cancer. Starting with the nonmetastatic data. The Niagara trial was a randomized phase three trial and the trial compared neoadjuvant standard of care, jamine and CISplatin. Compared to that plus peri operative di valley map. We know that neoadjuvant splatin based chemotherapy has been the standard of care for decades, whether it's gem cyst or dosen MVAC in muscle, invasive bladder cancer. However, half of patients recur and the question remains, can we improve on this uh long-standing standard of care regimen, the Niagara trial randomized patients with muscle invasive bladder cancer with either classic histology or actually variant histology. Patients were required to have a creatinine clearance of 40 or higher. Although patients with a creatinine clearance between 4060 received split dose CISplatin patients were randomized to either the standard of care CISplatin plus gyne or the experimental arm, which is GSIS. In combination with Derval and der vab was given both neoadjuvant and adjuvant. The primary end points were event free survival and uh complete response pathologic cr and a key secondary end point was overall survival. Looking at the baseline characteristics, most patients had good renal function. Tumor stage was about 40% T two and 60% greater than T two. Uh There was a good mix of PDL one high and low though most patients were PDL one high and there was about 15% of patients with divergent Histo Niagara met its primary endpoint of event free survival. Event free survival was superior for the combination arm with a hazard ratio of 0.68 P value of less than 0.0001. In addition, the event free survival favors the combination arm across all subgroup analysis. I want to especially point out that there was benefit among the PDL one low patients. So PDL one should not be used as a biomarker to decide who gets perioperative um immunotherapy also patients with divergent histology uh also appear to benefit the complete response rate. Pathologic cr was also better in the combination arm with an odds ratio of 1.6 at 37% versus 27.5%. Overall survival was also superior in the combination arm with a hazard ratio of 0.75. Favoring devala ma plus gem sis and A P value of 0.01. Again, looking at subgroups, all subgroups appear to benefit uh from the combination therapy. Looking at the adverse events and safety. The valley map was actually quite well tolerated adverse events leading to discontinuation of neoadjuvant chemotherapy were similar between the two arms and delays in surgery were also similar between the two arms. The rates of grade three or four adverse events were also similar between the two arms. Looking at the toxicities. Overwhelmingly, the toxicities were still driven by CISplatin based chemotherapy rather than by the immunotherapy portion which was relatively well tolerated. Although for example, with a bit more pruritus and uh and immunotoxicity. In conclusion, Niagara establishes a new standard of care for clot and eligible patients with muscle invasive bladder cancer per operative dalum improves event free survival, improves overall survival and improves pathologic cr rates compared to neoadjuvant gypsy that supply. Next, we have several other interesting trials. This is a smaller trial, a phase two randomized study by the Hellenic Geo group of nivolumab plus chemo radiotherapy in patients with nonmetastatic muscle invasive bladder cancer, not candidates for cystectomy. In this study. Patients underwent bladder preservation treatment with either conventional chemo RT with CISplatin or conventional chemo RT. In combination with the volume, the primary end point was LRFR. But this uh particular um data release looked at bladder cancer failure, free survival, bladder cancer failure, free survival was better in the combination arm compared to the standard of care chemo RT arm with a uh P value of 0.02 between the two arms. Overall survival was also improved with a P value of 0.01. This study shows that the addition of Neo TMT in this small randomized trial appeared to improve clinical outcomes. The trial is ongoing. This is an early data release and I want to point out as well that several phase three immunotherapy plus bladder preservation trials are ongoing including SW A 1806, keynote +992 and also sunrise two, which we'll talk about in a bit. Next, we have a really interesting study from Japan. This is an open label, noninferiority randomized phase three study comparing watchful weighty versus intra vesicular BC G in patients with high grade P one who achieve a PT zero on the second tur BT. So that's a lot of words. So here's the visualization of that patients who have high grade PT one disease and second tur if they achieve PT zero, then they are randomized to watch for waiting versus eight courses of inter BC G. Relapse free survival was the primary endpoint in this trial, relapse free survival was superior among patients. Uh well, excuse me, it was not inferior but numerically superior among patients who received watchful waiting. Compared to intravascular BC G. Overall survival was also similar and numerically better in the watchful waiting arm. However, there are some questions about this data. For example, intravesical relapse free survival was better uh trended towards being better in the BC G arm. There was also a rather high rate of metastasis events in the BC G group. Raising the question of whether the stage of these patients was actually maybe a little bit higher than T one in some cases. Next, let's look at some biomarker studies. We have some CT DNA data from the Tombola trial which thought to identify bladder cancer patients that might benefit from early post cystectomy immunotherapy uh versus no immunotherapy. Tombola was a national non randomized CT DNA based study. Patients underwent radical cystectomy after neoadjuvant chemotherapy and then had serial CT DNA measurement. We know from I and vigor 10 that CT DNA positivity was associated with recurrence and was also associated with benefit from adjuvant A TAI. The study asked the question of whether treatment with adjuvant taal lium could be limited to those patients who become CT DNA positive. The primary end point of the study was CR which was defined as CT DNA and radiographic negativity in patients who were CT DNA positive, converting to CT DNA negative after a tali looking at the oncologic outcomes. Not surprisingly, patients who are CT DNA positive at baseline after cystectomy did worse, uh which is consistent with prior data from iron vigor 10 and showing that CT DNA does associate with RFs and OS after cystectomy for the primary end 0.55% of patients converted to CR after Tas Aiza uh suggesting that TASI is certainly active. Although for this non randomized trial, uh bigger studies are still needed. I want to point out that there's an ongoing study enrolling across the country including here, which is modern in modern patients, uh will undergo CT DNA testing after cystectomy and depending on positive or negative CT DNA patients are being randomized to either a more aggressive or a less aggressive uh adjuvant regimen with the volume compared to either Neil rla or needle and surveillance. Next, we have additional data for EV Pembroke. This is an exploratory analysis of nin four expression and response to first line Ev Pembroke in advanced or metastatic urothelial cancer. We know from EV 302 that EV plus Pembroke is now the standard of care for most patients with advanced or metastatic urothelial cancer. However, we also know that informa doin is an antibody drug conjugate targeting nectar four. So it's a natural question to ask whether the benefit might be limited to patients who have high nect and four expression. What we see from this study is that this is not the case V pembroke was clearly better than standard of care chemotherapy regardless of high versus low neck and four expression for both PFS and for OS. And this data reinforces that V Pembroke um is a standard of care option in all patients. We have a few studies. Now looking at novel mechanisms here we have tar 200 which is a gemcitabine releasing implanted pretzel in the bladder. Uh plus cream versus climb alone as neoadjuvant therapy in patients with muscle invasive bladder cancer, who are not eligible or refuse neoadjuvant splatin based chemotherapy. This is the sunrise for trial. We know that there's an unmet need among patients who are CISplatin ineligible. Although we just saw that the new standard of care for patients who are cyst and eligible includes neoadjuvant chemotherapy plus perioperative dalum. We don't know what to do yet for patients who are cyst and ineligible cream is an anti PD one monoclonal antibody and Tar 200 is an implantable device that releases intravesical gemcitabine over a sustained period of time in this trial. Patients who are not eligible for neoadjuvant chemotherapy with splatin were randomized to Tar 200 plus cream or cream alone, followed by radical cystectomy pathologic. Cr was the primary endpoint. This study met its primary end point pathologic cr was 42% versus 23% in the combination arm. Uh with an overall response of 60% versus 36% for the safety profile. Most of the added toxicity from this gemcitabine released device was from urinary symptoms including dia polyuria, which I recently learned from Google means just polyuria, um urgency and hematuria. In summary, T 200 plus atrium ma had higher pathic cr and uh response rates compared to the trim alone. It's not known yet how this is gonna compare to perioperative develop A plus gem cysts for patients who are CISplatin eligible. The sunrise program has multiple trials ongoing. For example, sunrise one is looking at T 200 the sustained release gemcitabine um and a trim in combination in non muscle invasive bladder cancer. Sunrise two was stopped for futility but looked at this combination in muscle invasive bladder cancer versus chemo RT. Sunrise three is looking at the same uh sustained release gemcitabine plus or minus the trom versus BC G and sunrise five is looking at T 200 versus intra vesicular M MC or gemcitabine in non muscle invasive disease. The results of these trials remain to be seen. Next. We will look at a new drug. This is preliminary efficacy and safety of the Satna Vido with Pembroke in treatment naive her too expressing metastatic urothelial cancer. We know that about 60 to 80% of your filial cancers have at least some her two expression. The set medo is an antibody drug conjugate that is a her two monoclonal antibody conjugated to M MA E. So this is the same payload as in for ma via Cleve linker. In this non randomized study, patients received a set of a doin in combination with pembrolizumab, there was some encouraging efficacy data with an overall response rate of 66%. And as you can see in the waterfall plot, um all patients appeared to have some tumor shrinkage. We know that her two A CS have shown activity in neuroth cancer. Now across multiple studies among patients who are her two positive, there also is a tumor agnostic FDA approval uh which is trastuzumab dire A T can for patients who are her two positive with three plus her two expression. There are multiple trials ongoing of her two AD CS and this is an exciting space that will follow closely. Next, we have a different uh bici. This is EGFR and her three by specific antibody drug conjugate in patients with locally advanced metastatic urothelial cancer. This drug is a novel Egfr and her three by specific with a total one inhibitor payload. This drug in theory could target cancers that express either Egfr or her three, both of which can be expressed in neuroth cancer. In this early data, there was an overall response rate of about 41% which is encouraging in a heavily pretreated population toxicities from this drug were mostly hematologic. And it'll be interesting to see how this drug plays out over time in future studies. And with that, I will move it to Dr Belmont to give us some perspective and discussion on the urothelial cancer data. All right, Vince, an excellent job summarizing uh these uh these abstracts. And yes, the, the most striking one and the most relevant was the Niagara trial. Um Niagara trial was, was uh designed at the time that there were no effective second line therapies, acu immunotherapy was not available. So, um we're going to see how this trial is going to compete with the others that have been recently completed um with Nevo and Pembroke. Um But yeah, the, the the benefits in survival um and eventually survival is striking. And uh this is making us to jump to this as a as an option um whenever it is possible. So some, some, some uh things to consider is that uh this trial also included patients who were platinum eligible, but with creatinine clearance in between 4060 where you were allowed to give a split dose of this platinum. So that's uh an, an a thing to, to, to, to consider. Um And as mentioned, we will need to decide in the future if the other trials using uh combinations of IO um and ad CS um and other PD ones. Uh how are these going to compare with this trial? But uh as of now, I think it's a larger trial, 1000 patient trial. And this is absolutely definitely for the first time showing a, a survival benefit. So this is uh I agree. Um definitively. Um it's a new standard of care. Also, the point here is like uh it's not well um well defined if you have a, a complete response after chemotherapy, what to do all the patients receive adjuvant neval map. So, and this is something that in our mind, it, it doesn't make a lot of sense like to, to treat patients beyond um uh after new a chemotherapy if they go get AAA CR But anyhow, I think that the, the landscape is changing and um this is good to hear uh these um these results, the blood present basin trial that you have presented, the aligning group is interesting. It's preliminary, but as as you have mentioned, we need to wait for the, a trial on the keynote uh 992 in order to see if the adding immunotherapy do chemo radiation therapy is a good strategy for, for patients uh for blood preservation for the BC G trial versus uh what for waiting? I don't know how this was selected as a, as an oral presentation because it, it's like uh also the end points that were selected, they excluded patients uh recurring having T one or, or T A. Um I don't know. So I believe it's a non inferior but uh it's very questionable trial. And also the amount of PC T given was eight cycles. They didn't give maintenance, they didn't use re challenge. So it's quite questionable for the Tombola trial as as, as you have mentioned is a, is a single arm trial. And uh it's really interesting to see these 55% CRS. Uh And uh assuming that cr is the negativity of CT DNA and uh radiological negativity that is adding value that the monitoring patients with CT DNA is a is of value. Um But as mentioned with all these trials showing survival benefit, um how are we going to use AC DNA? How to because all the patients are going to receive immunotherapy in the end, right? So, um I know then we will need to decide what to do if a patient under um immunotherapy having a positive CT DNA, it becomes positive what to do next. So it's the field is changing and we will need to design more trials as the landscape is uh is changing for the biomarker Netting four. I think that this trial um they did select the, the cut off point at the median and we know that netting four is highly expressed. But one important thing that could have been presented for this trial uh for this analysis of the ev um uh throughout 302 is uh which faces having low netting expression do not respond. So it's small percentage of patients, but the cut off that day they selected that is 270 is pretty close to the high score. So, um and obviously, no differences were, were seen as mentioned, likely patients with low necking expression. There is some data showing that likely those are the patients that you like are not going to administer, even even Pembroke. So the other trial, the Sunrise four it it was for platinum ineligible. I don't know what, what this trial is adding. This trial was open at our institution and we decided not to put patients because there was no, no component of ay in these patients. So, um and yeah, the, the rate of, of, of, of pathology complete responses is 40%. That is more or less what you see um in uh even in patients receiving temporalis ma uh or other strategies and and the point is how durable are these responses. So I think more data need to come up. Although we know that the T 200 these um pretzel type of devices are innovative because it's a way to deliver intravesical um low dose continuous infusion of side of it. So I think that's uh it's an interesting device but likely better design trials need to be made in that uh in that space. And I don't know if that the setting is the right place to develop um this type of uh devices. And then yeah, the, the interesting thing that new A CS are are coming. Uh we have uh uh the satin that the interesting data on the satin. We uh so in this trial, it was shown that patients even having low her two expression. Uh Meaning uh 11 positivity, one plus I use the chemistry. So even the responses in low expressions was higher, 78% versus uh 66% in high expresses, meaning that maybe we don't likely having a minimal expression of her two, we will be able to use this. Um The study, the problem is that the is the payload is the mono our statin. So it's not an option to be given in patients after in for a doin. Uh So there is a first line trial ongoing. I don't know what, what's going to be the place if you need to like um score patients for her too. And finally, this new by specific, I think it's, it's it's attractive uh 40% of responses in patients that never receive an any A DC before. So it's, I think it's uh yeah, it's a, it's a decent response rate. But um obviously this trial would have need to be conducted uh in uh in second line after, for example, eb because the payload is a top of one inhibitor, meaning that you can give this compound in this second line setting. But I know that this compound is moving forward. There is a company that have acquired this compound and we are going to see trials designed uh with this um ETF R her three that is highly expressed in based on a study that was published in clinical cancer research in bladder cancer. So, yeah, the, the, the, the the field is emerging um more uh by specific, more ad CS coming. Um And those are good news for patients. Thanks so much, Doctor Belmont. It's, it's really exciting to see how much movement there is in bladder cancer. And I already, you know, four years after fellowship, everything I learned in fellowship was wrong. Agreed. Yeah. Excellent.
