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 2022.
Thanks everyone for joining us today. Um reviewing geo oncology highlights from Moscow 2022. Well let's uh dr sim pop day review bladder cancer updates. Take it away guru. Thanks. Thanks Jake. So thank you for the opportunity to discuss bladder cancer updates from escort 2022. So these are some of the key bladder presentations that I wanted to touch upon that I will go over Um in the succeeding slice basically the L. 15 BCG non muscle invasive study that I think is the only potentially practice changing study. And then the E. V. 301 update the javelin bladder 100 update on switch maintenance, Avila mob and then the prospect road to one data with cables and this article is a map and then or development as a component of new argument therapy. These were separate phase two studies And then some new data with the r. c. 48. Her two antibody drug conjugate. So coming first to N. 803. So this is an I. 15 super agonist which has properties of enhancing NK cell and T. Cell activity. And so this drug has been thought to potentially enhance BCG. Which led to this study looking at the combination of BCG plus N. +803, both given intra vertically in patients who were BCG unresponsive. And so the study was looked at in two patient populations. One is the customer mindset to population and then the second cohort was the popular disease population. Both BCG and responsive with the primary endpoint of cr at any time point in the CIS group. And in the popular group, the primary endpoint was disease free survival simply because in that disease you cannot really achieve uh you can achieve a cr waters in the C. I. S. Group. It's a little more challenging. So the demographics of this group are as follows. In the past, you know, Mine site a group around 80 patients per per cohort. As you can see most of the patients in the C. I. S. Group were C. I. S. Alone without other concurrent disease. And as you can see this was a heavily pre treated population. 16 courses of doses of BCG before getting on the study in the ci S cohort And 12.3 doses as the mean in the popularly disease cohort. So coming first to toxicities, this is a fully intra vertical regimen. As you can see the toxicity profile was very good. Really mostly minimal mild toxicities mostly from local intra vertical administration of both these drugs. So, coming to the casting of mine site a cohort. The cr rate at any time point there is was 71 which is quite impressive. The median duration of complete response was 26.6 months And the duration of response, complete response that is lasting 12 months or more occurred in 61.6%. This is 61.6 after cr patients. So really when you look at the whole pie, The one year cr rate is about 45% because it's 61% of the 71%. So when you look at the patients who had to undergo SAs teC to me to salvage the disease because of recurrence of persistence or symptoms. that was 16%. So that's impressively low. So the duration of cl was 26.6 months. As I said before and 36% of patients were still in an ongoing cr at the time point of reporting this study. So when you look at the results of the study in the carcinoma insitu group and compared with temporal is a map of course federalism have given intravenously which led to its approval in BCG and responsive C. I. S. The 12 year 12 months er rate is um Uh of interest is has been by based on consensus felt to be 30% or more. And with federalism that was actually not achieved 20% of patients achieved A 12 months. ER While with the n. A row three plus BCG 45% of patients achieved um cr at one year. And when you look at 18 months achieving cr this was 33% with the Enduro three BCG. And again the target of interest is 25% or more. Per consensus by paper published by Ashish Come out and colleagues and this was much lower 13% with Temple is a map. So really when you compare across studies of course in both of being both being non randomized studies but similar eligibility criteria. The enduro three BCD combination looks does look better although he started animates comparison. Obviously When you look at the papillary disease cohort, the 12 month disease free survival rate was 55%. So I'll get to the conclusions later. But I'm gonna essentially I'm showing you the data for the study. So these data I think that with any row three plus BCG look impressive enough that could lead to FDA approval and I believe the FDA will review it at some point later this year. Coming to the next 30 this is the long term follow up within photograph biotin versus chemotherapy in E. V. 301. The third line study comparing E. V. With taxi norman food in chemotherapy in metastatic carcinoma. So essentially the data held up the overall survival Improvement was stained with the hazard issue of 0.7 Median improving to 12.9 months versus 8.9 months. The median PFS also improved but I was Only 5.5 months within for the mob versus 3.7 months with historical chemotherapy. The objective response rate which we are used to seeing in format In excess of 40% of 41.3% Compared to 18.6% with mobility toxicity is no surprises. As expected. The neuropathy in the skin toxicities with the major toxicities. Of course you also see some minor suppression with Evie. Coming to the next 30. So again the E. V. 301 update is practice. Reaffirming I think so. Coming to the next javelin bladder 100 update. This is the switch maintenance Avila map phase three data of course which led to a change in practice a couple of years back. So this is the update which looked at it after long term outcomes with the median follow up of a little over three years. So in this there were a couple of posters presented and one of these um what was interesting was that 12.3% of patients were still receiving Avila mad with a median of almost three years. So that's interesting. There were patients on it very long term, so long term benefit In a small subset of patients and approximately 60% of patients who have discontinued did receive subsequent second line therapy. And this was a range of therapies as you can imagine, chemotherapy and fordham Ab and some of the patients were also receiving a different Pity one or L one and a beta as you can see. So really heterogeneous treatments. So long term survival improvement or benefit appear to be seen in patients with or without second line treatment based. All these groups seem to have a tale to them. So that's interesting to see. So the time from randomization to the end of second line treatment. So this is second and treatment after a while was similar regardless of the type of second line treatment. And among those who received second line treatment the time from end of available to the start of second line treatment was quite brief 1.35 months as you might expect, patients were mostly on and they progressed and received their subsequent treatment. So this is a separate poster that looked at long term outcomes in Javelin Bladder 100 based on prior response to the first line platinum based chemotherapy, essentially the benefit of survival was seen regardless of prior response cR pR or stable disease. What I found was interesting was that when you look at progression free survival in patients in the CR group and this is a group of patients who are Cr with prior platinum where we sometimes wonder if they need maintenance available. But if you look at this group, the median PFS with Ahmad Is only 9.5 months who is actually not that great. So, I think that really benefit was seeing regardless of the quality of prior response to the chemotherapy Coming to the next day. So again, this data of course, is practice. Reaffirming with the Javelin Bladder 100 coming to the next 30. This is cosmic 021 which looked at combination caboose antonym and caboose antonym given at less than full single agent doses 40 mg once daily with a T cell is made in metastatic urethral carcinoma. And this story has been presented before in different cohorts. But the three cohorts that was shown here were first line CISplatin ineligible. First line CISplatin eligible and then post immune checkpoint inhibitor therapy. There were approximately 30 patients per uh cohort as you can see here. Pretty typical population. So the response rate as you can see was 20 in the CISplatin ineligible group, 30% in the CISplatin eligible group And only 10 in patients who had received prior immune checkpoint inhibition. When you look at the median duration of response was around 7.1 months in the CISplatin ineligible group 4.1 months in the prior immune checkpoint in the group and was not reached in the CISplatin eligible group, which you can expect will be doing a little bit better than these other groups of course. So when you look at the regression of tumors, the majority of patients had some tumor regression across these three groups And the median progression free survival as you can expect was the best in the CISplatin eligible group 7.8 months and lowest in the prior immune checkpoint in the very group at three months. So clearly the caboose antonym artist realism combination is active. It's not clear if this, it really confers um some long term benefits and this I think will be clarified by the ongoing main cap trial that is combining a balloon with cables and and have been the switch maintenance setting In a Phase three intergroup trial setting survival again, no surprises, approximately 14 month median survival with the combination in the first line setting and in the project Continental listening. Eight months toxicities are as expected with A F plus PD L. One enable accommodation. So moving on to neo adjuvant therapy. This is a study which looked at, there are a couple of studies I want to present. One is the available study here. These there were two cohorts CISplatin eligible and CISplatin ineligible. The CISplatin eligible cohort was presented in at ehsmoh. There was randomization to James is back and previously the uh Pathologic response rate has been reported to be approximately 60%. This is less than T two disease. Petey two disease. This was at and at ASco this year the CISplatin ineligible cohort was presented in which there was randomization to a value map alone or paclitaxel gems that have been really bad. So no platinum in this chemotherapy backbone here. And interestingly the pathologic response rate was actually numerically higher in the US alone group 36% versus 18% in the packed gym in my group. But again, this is a very small story as you can see only 28 patients per group. So essentially I think that there These are interesting drugs to look at and Phase three trials are ongoing examining immune checkpoint inhibitors in both the CISplatin eligible and ineligible settings which will provide us the answer. So moving on to CISplatin eligible muscle invasive bladder cancer. This is a study which looked at gems is combined with development as new management therapy followed by radical mastectomy and then followed by a jew in development. The difference between this phase two study, this is a phase two non random s terry difference between this and the other report studies is that the primary endpoint was F. S. Not. That's er So looking at it, it's a different endpoint. At the end of the day they enroll approximately 60 patients um when you look at the activity no surprises. The paths here P. T. Zero rate is 34% and less than P. T. To rate is 60%. So really in the neighborhood of where all the other jem says. So CISplatin chemo plus pd one L. One combinations um have shown activity the toxicities again, no surprises. And the event free survival was impressive 76.1%. And the survival also was impressive. Again we did more mature follow up. There was a correlation of pathologic response with two year E. F. S. And there were patients who are not positive who were enrolled on the study by the way and patients who had pathologic not positive disease. Following the idea of chemotherapy. Chemo therapy had poor outcomes as you might expect. So moving on to a novel her to binding antibody drug conjugate. So as you know we have T. DM. One trust is a map director can And now we have a drug here. r. c. 48 that was presented. This is an antibody to congregate that resembles test is um a direct stick and targets her too and has a livable linker so that the drug is released in the micro environment. Also this was designed with different toxin payload M. M. A. As opposed to direct stick an which is a is one enabler. So potentially timberline toxin is more active in europe given the history of urethral carcinoma, responding well the most turbulent targeting agents. And then the her two binding agent monoclonal antibody was designed to have a higher binding affinity for her too. So all these theoretically might make this drug more active than test is a map directly can in carcinoma. So there were three abstract presented all from china. This was a chinese study. So there was one abstract looking at the whole two positive population, one of the her two negative population. And there was a third one that looked at the RC. 48 A. D. C. Combined with an immune checkpoint inhibitor. So the poster that looked at the her two positive population defined as her 22 plus or three plus. So in this group There was a response rate of approximately 50 In 107 patients. Again this is a non random mystery When you look at somewhat better selected patients. I had c. three plus or two plus plus fish. The response rate was better 62%. And again this is a somewhat heterogeneous group of patients. Uh These were post immune checkpoint inhibition but in about half the time but not always. And then a separate abstract looked at the her too Um low population which included her 20 or one plus. This was a small cohort. There were 13 patients who were one plus for her too And only six patients who are zero. And essentially in the Ice zero group Nobody responded to r. c. 48. But in the her too low. But one plus group about a third of patients are responding here With our c. So that's interesting. So there might be activity in the her two low group and of course predicated on the fact that the livable linker releases the toxin payload into the micro environment and has activity beyond her to beyond the mechanism of needing her two expression for activity. So the toxicities are quite similar to what we would expect with M. M. A. E. The neuropathy rash somewhat like we're used to Within Four to map. So that way it's different from Testes Map. Did you can I'm coming to a third poster with RC 48. This is r. c. 48 plus Tory Palin mob which is a pd one inhibitor. And this study was non randomized and looked at metastatic carcinoma Regardless of her two expression. So they were all levels of her two expression and even her 20. The overall response rate is quite impressive, 71.8 Denominator is 39 patients. And of note patients would occur to two plus or three plus. They had an even higher very impressive response rate 86%. So this is an interesting um combination based on this I think as you can see the response right here rivals PVP embolism Ab which is which was an un celebrity patients. But this study also was essentially the her to abc RC 48 Tori paloma was also an unsolicited patients because they allowed any level of her two expression including her 20. So really this is an interesting combination. I think this we need for the data. Again it's a small 30 of 39 patients with the r. c. 48 Plus Tori Palamar. c. 48 also called the city mob. Now I guess when they start naming these trucks could be more interesting. So just to summarize the studies presented here, I think that the only practice changing study potentially is the L 15 super agonist N 803 plus BCG for BCG. Unresponsive non muscle invasive bladder cancer. There was an excellent therapeutic index 71% cr rate. One year cr rate of 45 And the duration response 26.6 months. The E. V 301 phase three trial our practice reaffirming and confirms the previous data we have with gelatin in the third line setting. The Javelin Brother 100. Phase three trial update I think. Reaffirms then further solidifies the role of maintenance available including in the prior CR group with prior platinum based chemotherapy and then the F plus PD L. One combination with cabo arches. Oh clearly had activity but we need randomized data. And the phase three main cap trial in the switch maintenance during will hopefully provide that data. Remember that Land plus federalism ab as first line therapy in mostly somewhat sick platinum ineligible patients was negative. President Reggie us earlier this year and then a new management therapy, immune checkpoint inhibition will probably have a role hopefully. And the phase three trials are ongoing. There was interesting and the odd 48 A. D. C. Is clearly an antibody to congregate to keep an eye on based on the interesting activity scene with this drug In the her two positive population. Uh and in fact even in all comers in combination with PD one and a beta. So I think I'll end there
