The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the genitourinary cancer clinical updates you need to know from ESMO 2022
If you are just joining us we're discussing geo oncology updates from Asthma 2022 Dr. Mantia will be discussing updates in bladder cancer. Alright. Hi everyone. Thanks for joining. So I'll briefly go through the bladder cancer updates from is mo and then we're fortunate to have joking Belmont to comment on his thoughts. There was not a lot practice changing in bladder cancer. Um But the important updates from the E. V. 103 which I'll talk about two other studies and then briefly talk about some ongoing biomarker work. So these are disclosures. So to start with E. V. 103. So the update from cohort K. Um which was a randomization for patients with locally advanced or metastatic disease who were CISplatin ineligible. They were randomized 1212 E. V. Monotherapy or E. V. Plus Pemberley is um um um same dozing of E. V. But just on days one and eight of a 21 day cycle and embolism ob on day one This was our standard patient population um of you know mainly um men in their seventies of note there were 30-40% upper tract disease in the study. And then um most patients about 85% in the combination with the visceral disease. And so the objective response rate for the combination of E. V. Plus Pemba was 65%. Um And 45% in the monotherapy arm which is consistent with prior studies for the combination. There was a 10% complete response rate. Um And you know less than 10% of patients had primary progressive disease. And um the responses that we're seeing, we're really rapid. So 86% of patients who responded, um you could see that response on their first scan at nine weeks. The response rate was consistent across all subgroups. And even in patients with liver mets, which is a difficult to treat patient population, 54% um had an objective response. So here's our waterfall plot, fortunately it's very lopsided here with 97% of patients seeing a tumor reduction. Um This also shows that responses we're seeing really regardless of Pd L. One cps score. So you can see in orange cps greater than 10 in blue less than 10. And um really responses were regardless of of the score. Higher, low. So duration of response was not reached in the combination arm. Um and was 13 months in the mono therapy arm For median progression free survival again. And the combination was not reached. But 55% of patients had not had any progression at a at a year. And in the monotherapy arm, median progression free survival was eight months pretty similar to prior studies, median overall survival for the combination was 22 months And 80% of patients were still alive at 12 months for the combination. And so here's showing necked and four expression um in the tumor. So as you'll recall, evey is really targeting antibody drug conjugate against next. And four. And the vast majority of bladder cancer shows next and four expression. So for patients who had tumors that were a valuable 95% had um next and for expression. But you can see even in a few patients who didn't have necked and four expression there was still some responses seen um in the combination. And so for treatment related adverse events there were no new signals with the combination. You know there were the side effects that we would expect from each drug individually. So fatigue, neuropathy, alopecia and rash. Really the thing to pay attention to is rash since that's an overlapping toxicity among Tv and pem bro. And so you can see here in the combination arms 17% had grade three or higher treatment related rash. Um There were some treatment related deaths three and two in each arm related to human itis, respiratory failure, organ failure. So overall, you know this confirms encouraging data for the combination of E. V. And pembroke especially in the CISplatin ineligible group that we're looking at. So Next I want to briefly discuss the recent trial. So this is a phase two study looking at preoperative radiation therapy combined with immunotherapy um prior to systemic to me for patients with locally advanced your othello carcinoma. They were mainly target targeting a CISplatin ineligible group which we'll discuss. So these patients had locally advanced disease. So they had to have clinical T. Three T. Four A and or node positive disease. Um technically they had to be CISplatin ineligible or CISplatin refusing. And so the treatment was d'Avola mob every two weeks for four doses. And during this time patients received radiation to the pelvis to 45 gray, plus then a boost to the bladder to 5.4 gray. After completing this patient then underwent radical mastectomy between weeks 11 and 15. And this was really a feasibility study. So the primary endpoint was completion of treatment. And so that the percentage of patients who completed this treatment and underwent a mastectomy. The secondary endpoints were then response toxicity and survival. And so this patient population um of no really the patients that they enrolled, only 30% were actually CISplatin ineligible. And so the vast majority of patients in the trial were CISplatin refusing. Um and this was a locally advanced patient populations of 30% had clinical node positive disease. So this study met its primary endpoint. So 87% of the patients completed the treatment. Um really only four of the 31 patients didn't successfully complete treatment because to have a delay in their surgery beyond 15 weeks and then to only received one dose of NovoLOG mab. Um in terms of the secondary endpoints, there was a 70% response rate. So you can see um 58% of the patients had less than muscle invasive disease on their systemic to me path. Um and the disease free survival rate at a year was 90 For treatment related adverse events. The majority really most significant was diarrhea and then there was thyroid and skin toxicity. 25% of patients had to stop NovoLOG during the treatment due to adverse events. Um and so I think this is a small study, small number of patients. It shows that this approach is feasible and safe. But we really need more data to show how efficacious this is in this patient population. So next I want to take a look at the bladder path study. So this is a randomized trial. Looking at M. R. I. As opposed to our standard um cyst Oscar P. With T. R. B. T. In order to stage muscle invasive bladder cancer with the goal of trying to expedite treatment for these patients. So in the, you know, standard pathway and how we basically diagnose and treat muscle invasive bladder cancer. There's often quite a delay. And so you can see in orange this is our standard pathway. So patients undergo an in office flexible Sista ska P. Um They see that there's a bladder tumor there then scheduled to come back for a surgical tur Bt. And then once the pathology from that results, patients then get the appropriate treatment. So if it's non muscle invasive disease, they've had their T. R. B. T. And they can get a judgment treatment if it's found to be muscle invasive, they then can undergo their definitive treatment of chemo radiation or surgery or a combination of these. Um This study was looking at trying to expedite this pathway and skipping the tUR Bt from muscle invasive patients. And so patients underwent an in office flexible cyst copy. And then they asked the urologist do you think that the lesion is non muscle invasive equivocal or muscle invasive or lesions that were thought to be non muscle invasive? They were scheduled for tUR Bt. And for lesions who that were equivocal or thought to be muscle invasive. They first underwent M. R. I. Based on the results of the M. R. I. If it was non muscle invasive, the underwent tUR Bt. Or if it was clearly muscle invasive, they could go directly to definitive treatment and skip the trb t. The goal of this was to try to reduce the time to correct treatment. So the primary outcome was a reduction of at least 30 days in time to correct treatment. They also didn't want this pathway to um basically delay treatment of non muscle invasive disease. And so the secondary outcome was time to correct treatment for all patients and for non muscle invasive disease. So you can see here in red is our standard approach that we do currently and in blue is the experimental arm. And so for the standard approach where all patients get it to you. R. B. T. The time to correct treatment is about 100 days. Um And that's pretty consistent to what we see in the real world and for the patients who underwent M. R. I. They reduce this by half. So the time to correct treatment was 53 days. Looking at the secondary out outcomes the time to correct treatment for all patients. So the non muscle invasive disease patients was about 30 disease 30 days. So you're not delaying their treatment by doing the M. R. I. So just to comment on that briefly I think you know this is um you know interesting data. I think there's a long delay and a lot of patients to getting treatment but we have to decide how comfortable people are with going directly to definitive treatment without path confirmation of muscle invasive disease. So I think more work to be done here. But I think M. R. I. Overall is very helpful um in the management of these patients. So briefly I just want to look at some biomarkers. So there were multiple studies um we're trying to sort out in bladder cancer who should get immunotherapy and when um you know which patients up front can benefit from immunotherapy and then which patients are we really benefiting with a value mab maintenance. And so this data here is looking at um the javelin bladder 100 of maintenance of Valium ab and trying to see who's benefiting in this setting. Um And so you can see here this is a mutation burden low versus high. And so you can see for tumor mutation burden, low patients there really wasn't a benefit in survival for a Valium ab maintenance over best supportive care for patients who had TMB high, there was a significant benefit in overall survival with the hazard ratio of 1000.53. They also looked at tertiary lymphoid structured gene expression. So for tumors that had high tertiary lymphoid structure gene expression, there was a benefit again seen with a value of maintenance over best supportive care. Um And for patients who had a low TLS gene expression that really wasn't much of a benefit. We then looked at or um dr paulus who presented this, looked at how to f to gene expression in the tumor. And also um the presence of chrome button loops to Pao two F two in the blood. And so power to F two is thought to be associated with a T. F. Factor's signature and potentially an increase in tertiary lymphoid structures as well as um dendritic cells. And so um when these tumors had a high powered two F two gene expression, there was again a benefit seen with a value map where there wasn't um for a low gene expression similarly, when the chrome button loop was absent, which means a higher gene expression, there was a benefit seen but not when the loop was present. This is important because in looking at a tumor mutation burden low group. Um There was a subset of TMB low patients that had um absence of the power to have to promoting loops. So um hi gene expression that um showed a benefit to the Valley Mount maintenance. So most TMB low patients did not show a benefit. But if they had this absence of the power to have two pro maten Loop, there was a slight benefit seen. Now all of this is exploratory especially with this group here. There were low numbers 18 and 22 patients. So this is all hypothesis generating. But I think in general we're getting closer to hopefully finding some biomarkers to really personalize treatment in this space. So I'll just end with um looking at one more biomarker study. So this is looking at the bigger 1 30 study. So this is frontline. A. T. Cell is a mob versus chemotherapy. Um In patients with metastatic or advanced your othello carcinoma. And so this study was looking at different pD L. One biomarkers. So currently we use and it is a map is approved for the S. P. 142 Pd L. One expression biomarker. They were looking in this study also at cPS scores and whether these deferred um in outcomes with first line chisel is a map. So the S. P 142 biomarker um is thought to preferentially stain immune cells and co localizes with dendritic cells. So is thought to be a better buyer marker. And as we see here um for S. P. 14 to 0 to one pd L. One. Um There was no benefit to frontline at T cell is a mob but in looking at um you know I see 23 higher Pd L. One in this patient population. There was a benefit to frontline A T. Cell is um um and this is in the CISplatin ineligible group in which for platinum ineligible patients or for um CISplatin ineligible patients with high PD L. One using this assay you can use a T. Cell is a mad. So for the CPS score greater than 10 or less than 10 there really was no benefit in these groups to materialism and frontline therapy. So just to wrap up with some conclusions you know I think Evey and Pem bro um is the big highlight from this study but is basically just confirming data that this combination is showing encouraging efficacy and is likely to become a frontline treatment option especially for CISplatin ineligible patients. And then there's ongoing studies um The next for preoperative radiation therapy plus immunotherapy you know this approach is feasible and safe but we really need bigger studies and more data to think about how to use this and if it's a benefit and then M. R. I may help accelerate the treatment of muscle invasive bladder cancer during the work up. And then there's many biomarkers under under development to help guide our treatment approach especially with respect to immunotherapy and combinations in this patient population. Okay so I will turn it over to Dr Belmont for comments. Yeah I'll just dr Belmont before you get started I'll just say to the group if if any questions put them in the chat or the Q. And A. Otherwise we'll turn it over to dr Belmont. I have one Joachim and Charlene. Very nice presentation, Charlene. The TMB signal in javelin 100 signature. The 101 signature which is a renal signature. That's the problem. Really very interesting. I'm surprised you know with the drug you know um expensive like this who to my knowledge given as maintenance until progression. You know the TMB single signal is extremely strong. That this has not picked up more you know and this was an oral presentation. Right? Yeah. Yeah. This has not picked up more. That's I mean I understand but that's the biggest uh you know a big news I mean don't know Joachim also I think that they are doing uh an outstanding job with development. Like using the as you mentioned the kidney signature here in in the in the development in this maintenance space. And they also so when when he presented that they did the correlation with the signature with these epic atomic groups that it is in fact. So this is done in in in bristol um lymphoid cells. Um so I think that this is very exploratory I think that this is an absolute I was caught or this abstract. And the final version was sent like one day before I was so and so it's it's a but it's interesting that this signature obviously cannot be translated to the daily clinical practice because of the feasibility of using this signature for these patients. Um And because yeah TMB likely is much more easy to get that. They have been doing this artificial intelligence analysis using clinical factors like uh like uh D. N. A. A. RNA analysis and and also um immuno chemistry. Um But you know it's interesting that the outstanding work that is being done. So um yeah. So what going beyond that the nice thing of this presentation the power is like in in producing the epa genetics in the prediction of immunotherapy response. So even if it is in term line is using these loops. Using these epic switch that is like a commercial available way to measure the commenting loops. Um and then this how to have to that nobody knows which type of gene, well it's involved in the development of lymphocytes B but it's not not a clear defined role. So it's that impressive data just um really impressing the TMB should have taken. Thank you because TMB is easy. I know they put the median chris asked a very good question. What was the median overall. But this is very interesting. I haven't seen anything you know that. And if you look at the number there in very small character between BSC and with BSC this is not like five patients. This is equally distributed. Absolutely. So that they used a different measurement of TMB but it's equivalent to a limitation for negatives. So yeah. So I wonder if we could ask tom to make a signature that is TMB high and Javelin immuno high won't be many patients but that could be the most because that's that's really interesting for the sake of time. We're gonna have to wrap up in a moment. Dr Belmont. Did you have any other comments about the other studies you want to make? So I think that the most interesting presentation that the V. 103 as you know the cohort A. Has already been published in J. C. O. Response rate 73%. PFS 12.3 months. So that this was the E. B. 103 cohort K. Was a randomized in a patient population highlight the high rate of response That the at 12 months 65% is still responding. But yeah the point to raise here is that um very friendly rapidly. Any grade 51% of patients serious treatment related to birth events in this unfit. First line patients? 23%. Uh And that's due to a treatment for 4%. So likely that's obviously interesting combination. But we need to like wait obviously the the results of the randomized trial the three D. 02 to see how much benefit is obtained and obviously the balance on toxicity it's important and what's going to be the place of pembroke if this is positive in first line compared to giving patients who are unfit parents For example by maintenance development. Maybe we'll need to redefine this population and select patients better for which which therapy needs to be used in first line. So I think that I would not jump immediately to Dipendra in a patient. So but we need to pay attention on this type of side effects neuropathy in 5050% of patients and those patients will not be able to receive platinum later on or any other potentially neurotoxic uh combination. So it's a great yeah that's a great point. Um Thank you.
