Chapters Transcript Video Updates from the 2020 ASH Meeting: Chronic Lymphocytic Leukemia Ash this year, felt a little bit like that movie, the Matrix Virtual Ash. But actually for for me I thought it worked pretty well, it was really great to be able to see all the sessions I wanted to see and we had a lot of data in CLL that I'll review with you, so let's jump right into it. Uh just ends here, Yeah, here we go. Uh these are my disclosures. So just to set the context for CLL, this was a great review from Jan Berger last year in the new England Journal of Medicine and you know, we had several decades where there were some incremental benefits of different chemotherapy regimens and then the development of chemo immunotherapy in around 2010. But really, as I think, you know, the last decade has been revolutionary for CLL, starting in the early part of the decade, with the development of single agent uh inhibitors of the B cell receptor pathway, the BCL two antagonist veneta clocks. And really over the last few years it's been about sort of defining the role of these novel agents both in front line and relapse setting compared to our current standards of care at the time which was mainly chemo immunotherapy. Big readouts at the Ash meeting over the last couple of years for example comparing a brute nib to standard chemotherapy regimens. And you know really in the last couple of years where things have started to get particularly exciting I think is combinations of novel agents and starting to compare novel agents to each other for example. And so we started to see some of that data at this Ash meeting and just to quickly remind you about the path of physiology here. So a lot of the action in CLL is in the lymph nodes. These are where cll cells can proliferate and grow. And the cll cells are really nursed by a variety of stromal cells such as nurse like cells and T cells which can send in these pro survival signals to allow the CLL cells to proliferate. And the drugs that we're talking about here. The BDK inhibitors, the P africanus inhibitors are really interrupting that the cell receptor signaling pathway that's sonically activated in the CLL cells. And in the lower right panel, see there you see the BCL two antagonists, Panetta clocks which can target right at the level of the mitochondria, highly effective at killing CLL cells. And has been used particularly in the combination setting with anti cd 20 monoclonal antibodies. So with that brief background I'm going to dive into a lot of the data from ash 2020 kind of dividing this up by frontline studies. First we'll talk about four of them and then moving into the relapse refractory setting. We'll try to get through a number of different studies which I think are impacting our thinking about the disease and in some cases changing our practice. So let's start with treatment naive Cll. The CLL 14 trial is one that you may be familiar with. It's been presented a number of times now and was published in the new England Journal in 2019. As a reminder, these are front line CLL patients, most of whom had some comorbidities or older and were randomized 1212 a one year course of veneta Clacks with abilities a mob in combination for the first six months. And that was compared to a 12-month course of Clara Basil with open into the mob with a primary endpoint of progression free survival. And a number of different M. R. D. Assessments were made throughout the course of the study. They did serial testing of M. R. D. At three month intervals and used the adaptive Kelowna see gas A, which is the next generation sequencing based essay that goes down to a level of 10 to the minus sixth, Which looks certainly a lot more promising in terms of its predictive power as compared to standard flow Saitama tree, which looks at 10 to the -4. So at this ash meeting, the update for CLL 14 focused a lot on the clonal dynamics of M. R. D. Particularly in the veneta clocks amenities a mob arm. I pulled out this slide, which I found particularly interesting. If you look on the left side, you can see a little bit of a busy uh diagram here. But the column on the left is the M. R. D. Assessment at cycle seven day one, which is about halfway through the year of veneta clocks. And the different colors here represent different depths of M. R. D. So the darkest green is 10 to the minus, less than 10 to the minus six by NGS, the lighter green, 10 to the minus fifth. Uh and then 10 of minus forth etcetera. The orange and reddish colors are detectable M. R. D. And then the column on the right here is follow up month three meeting three months after completing the one year of therapy. And so what you can see is that for the majority of patients, particularly those who still had detectable MRT halfway through most of these ribbons are kind of heading down suggesting these patients did get deepening response with additional six months of veneta clocks therapy. Well interestingly you do see some individual patients where those ribbons are headed up and some patients actually had developed rising M. R. D. Levels either during or within three months of finishing therapy. And so one of the key questions with this veneta clocks abilities and that regimen is really what is the right length of therapy? The design of this study was one year for all patients and a lot of people have fairly asked the question well, you know, do some patients maybe need more veneta clocks? Maybe some patients could get away with less. So this update doesn't directly address that question. But some interesting indirect information comes from the middle panel here where you see kind of the left part of that suggests that between that midway point and post therapy, about half of the patients with detective marty actually had rising Rd while still on banana clocks therapy. This is a group where you would not expect additional veneta clocks to be helpful since they're already sort of progressing at least by M. R. D. While on therapy. But in contrast, the other 50% actually did have decreasing M. R. D. Well on Vonetta Clark therapy suggesting perhaps this is a group that could benefit from even longer therapy than one year. So future studies are going to be needed to really help define the optimal length of nine o'clock space therapy in the front line setting. I do think it's probably going to need to be individualized for patients based on M. R. D. And on the far right, you just see an update of the Mardi data which did show about 74% of patients achieving undetectable M. R. D. By NGS. So very impressive numbers with this regimen. And they also updated the clinical data in Cll 14 with four year follow up. Now you see the median PFS has still not been reached with the nine o'clock seven to some Abbots, about 74% at four years. If you remember from last year's ash, it was 82% of three years. So in other words, only about 8% of patients have had progression despite being off therapy with this additional year of follow up. Certainly a very active regimen for our CLL patients generally well tolerated, although it does take some work to get patients started with the veneta clocks ramp up. Okay, so another important data set that's been evolving in CLL is the captivate study. We've previously seen presentations of this trial from fixed duration cohort. This is a brutal and plus veneta clocks in the front line setting. This is a multi center study in younger patients. Everyone had to be under the age of 70 but included all different criteria for risk factors as you see on the right. So median age in the in the fifties. Generally uh number of patients with higher risk disease with deletion 17 P. And a mutated I. G. H. V. On the left. You see the treatment scheme a c 164 patients and they started with a broom and a bleedin for three months to side to reduce and then they get a combination of a broad nib plus veneta clocks for one year. And what's different about this cohort which was presented for the first time at this ash meeting? Is that at that point after the 15 months of therapy the patients are randomized. If they've had confirmed undetectable Mardi, after that one year they get randomized to either placebo or a broad nib. If they don't have undetectable M. R. D. They get randomized two additional veneta clacks or just a brunette. And the primary endpoint of this analysis was one year disease free survival. In those patients who had confirmed undetectable M. R. D. You can see that on the left, that's the disease free survival curves, No difference whether they got an additional year of a broad nib or not. Uh So certainly reassuring that there can be some good durability to that 15 month therapy even even a year later. Although the follow up there is quite short on the right side. You can see in the patients who had detectable M. R. D. At the end of that 15 months and went on to get additional uprooted plus fanatic lacks a deepening of M. R. D. Both in the bone marrow and peripheral blood. Uh For example in the bone marrow, only 31% of patients had undetectable M. R. D. Uh At the beginning of that time period and then after an additional 12 cycles 34% more of the patients achieved undetectable Mardi. So In that group there may be some benefit to that 2nd year of therapy. But in total I thought it was interesting at the bottom there at the table. The 30 month PFS was really about the same for all four of these different groups, 95 to 100%. So I think this speaks to the fact that this is a very effective regimen and the follow up is short. You know, we may see some differences emerging PFS over time but certainly not yet. And just to highlight the tolerable itty of this regimen was reasonably good. You can see on the left there are quite a few a any great 80s including some of the ones who are accustomed to seeing with a broad nib like atrial fibrillation, hypertension and and some bleeding events and infection. Although the rates as you see on the right of Grade III or higher, 80s were pretty low at this regimen. So I think overall this is an important combination. There is an ongoing registration study called the glow study comparing ivy to clear imbecile amenities. A mob in older patients. That is likely to lead to a label for veneta clocks in CLL probably later this year. So although the captivate study itself was not practice changing, it's likely that the glow study will be. Although I would say there are still some liabilities with these types of combinations with a broad nib, particularly around the cholera bility of this regimen. Remember that captivate here is a younger fit population, so we worry a little bit as we use a brute nib and the older population, particularly with cardiovascular comorbidities that we may run into more issues with toxicity. So that in part has been the inspiration for the development of a study that we've been leading from Dana Farber. An investigator initiated trial of the more specific b t k inhibitor, a caliber nib even with veneta clicks and also abilities a map. So triplet regimen here we call this the evo study. It's a phase two trial front line CLL open initially to all comers. Although recently we've restricted enrollment to patients with TP 53 aberrant disease where we really think we might see the greatest benefit from a triplet strategy. We updated our data at this ash meeting presenting the 1st 44 patients. And you can see here this is a population that's still on the younger side, median age 63 but we did have some patients into their seventies on the trial, about two thirds mutated Igh V. And importantly our data set is really enriched for the tp 53 aberrant population in close to 40% of the patients, a high risk group on this study. And you can see the schema here where we start with a month of a calibrated monotherapy. We get a couple of months of Bennett Osama bin in combination with a calibration iB to do an effective cider reduction. And then we start the veneta clocks ramp up. We did actually slightly shorter veneta clocks ramp up here four weeks instead of five weeks to try to make it a little bit simpler. Uh And then we did the triplet therapy followed by the A. V. Doublet. So again a total of about 15 months of therapy to try to match what we've been seeing from other studies. For example, like captivate The primary endpoint. Here is the bone marrow undetectable. MRT rate with cr after that 15 months of therapy, just briefly on the safety profile. Overall, it looks quite favorable with the three drugs. We did see grade three or higher neutropenia and about a third of patients. But otherwise, if you scan down that column of grade three or higher toxicities was pretty low. Uh We do see some headache with a caliber pretty commonly tends to happen early on. But for most patients we can get them through that fairly easily. With supportive care. We did see about a quarter of patients with some infusion reactions from abilities of mad, but only one case of a grade three or higher infusion reaction and very low rates of infection. For the cll population, we had only one, grade three or higher infection, only one atrial fibrillation, grade three or higher and very little hypertension. So very well tolerated combination, interestingly, we saw a little bit of laboratory analysis syndrome when starting a business is a mob, which was early in the course of the study, we did not see any TLS with the four week nine o'clock ramp up and we saw a very effective cider reduction with the doubling of a calibration of openness is a map and you can see that with the pie chart here. So where is that? The study? Entry 94% of the patients would be considered high risk for TLS with veneta clocks based on their tumor bulk. By the time we actually started the Veneta clocks after three months of a calibrated. Haven't opened it to the map, 91% of the patients had low risk for TLS, which made it easy to administer the clocks ramp up in the outpatient setting. These are the preliminary efficacy data on the left is I. W cl response in all patients and tP 53 aberrant patients, about 40 45% of these patients are achieving cr after 15 months. And on the right, the undetectable MRG rates are quite high. So 84% undetectable M. R. D. In the peripheral blood. And similar numbers in the TP 53 aberrant patients, quite a few of the patients now have have electively stopped therapy after completing 15 or 24 months and no patients have had progression of disease or even recurrence of their M. R. D. At this point. Uh A couple things to highlight here. One is that there's now a phase three trial that includes a vote is one of the arms Avio versus A. V versus Chemo immunotherapy which is ongoing. And I'll just highlight also that our own Eva study here is is still ongoing, restricted to T P 53 year deep or deletion 17 p patients. But if you do have such CLL patients in the front line setting would be very happy to see them and try to get them on this trial. And then I wanted to just briefly update the data for santa brought neB. This was presented by my colleague, Jennifer Brown. Zanna Britain is another one of the more specific B T K inhibitors with a very favorable safety profile and a good initial efficacy profile in CLL. This is our MSI of the sequoia trial. Sequoia is the trial that hopefully will lead to an FDA approval for Xander brunette in CLL uh, that's got a randomized component to it, an arm A But here the results of our MSI are being presented which is specifically the population of treatment naive deletion, 17 P patients. This is actually one of the largest cohorts of 17 p patients ever reported in the front line setting. Over 100 patients, median age of 70 who all received Santa Brightness as monotherapy. And you can see here that the overall response rate is close to 95% with very promising progression free and overall survival. So an 18 month PFS of about 90% in this high risk population with 17 p deletion I think looks very good and like with a calibration of the safety profile of Zana Britain looks quite favorable. Although you see some infections as is common in any patients with CLL. Uh the rates of atrial fibrillation, major hemorrhage hypertension are certainly a lot lower than what we're accustomed to seeing with that broad nib. And so I think santa Britain is going to be a helpful drug for us in Cielo once it's approved. Uh it's probably helpful to think of it as being more similar to a calibrated although there are some nuances that that distinguish the two drugs. For example it's hard to use a calibrated with proton pump inhibitors due to a drug drug interaction. Susanna Britain may provide an advantage there. Santa Britain have also has a label with daily dozing. Instead of the I. D. Dozing it can be given either way. Whereas a calibration it requires B. I. D. Dozing. So I think both are going to be great options for CLL patients. Okay so let's change gears a little bit and talk about the relapse refractory setting and I'll update you on a study that you're probably familiar with the Murano study. It's been presented several times now. Was published in the New England journal a couple of years ago. But for good reason, this is a very important study in the relapsed population. So nearly 400 cll patients. This is a little bit from an earlier era at this point, these are patients generally who had had a median of one prior line of therapy which was generally chemo immunotherapy. So very few patients on this trial had had prior novel agents And these patients were randomized 1-1 to either a two-year regimen with about six months of Veneta clocks for tax map combination followed by 18 months of Veneta clocks monotherapy. And that was compared to a standard six month course of Benham Austin where talks about and you can see that the primary endpoint here was investigator assessed PFS although they also nice job of collecting serial M. R. D. Uh we continue to get some interesting data from that. So, to me, the most important aspect of this updated at the 2020 ash meeting from murano was the five year clinical data because for the first time we've now seen a median PFS defined for the veneta clocks riTUXimab arm, it's 53.6 months. So clearly still better than the mustang and riTUXimab. But I think helpful to just have that number roughly in mind that Remember, this is about a two year regimen. So on average patients are going to years on therapy then they're going another 2.5 years or so off therapy and staying in remission. But eventually, you know, many of these patients are beginning to progress and we're starting to get more information actually about how how these patients are doing with their next line of therapy. But before I move on to that, just one other thing to highlight on the right is that we have previously seen this overall survival benefit in the earlier analyses. I think it's important to see that this is holding up at five years. There's about a 20% absolute improvement in overall survival and the patients who got the Veneta clocks, as opposed to be our. And although this study did not formally allow cross over most of these patients who progressed after BR did go on to get other novel agents, actually, in most cases it was a broad nib some of the patients actually did get veneta clocks. Uh nonetheless, you still see this profound improvement in overall survival. So to me, this really emphasizes that we should not be using Byetta musty and riTUXimab for relapse CLL patients whenever we have access to Vonetta Clark space therapy, because we really may be doing our patients a disservice if we're reusing chemo immunotherapy. And I think this really even applies for patients who have had long remissions from initial chemo immunotherapy often get that question. But this study included many such patients. And really the benefit was very clearly in favor of the clocks. So some very interesting data emerged from the M. R. D. Analysis on the updated murano study here at the top. You can see in the pie graph that at the end of treatment about 83 of the patients in the green had undetectable MRG, there were some other patients who had low level M. R. D. And the yellow. And then there were high MRG patients detectable MRT in the red. Uh and then if you look over time you can see how the pie charts change and it helps to give us a sense for the kinetics of first of all. How long does it take to go from having undetectable M. R. D. Two so called M. R. D. Conversion to having detectable M. R. D. You can see from the Kaplan meier curves on the top right median of about a year and a half. And then you can see how long it takes to go from M. R. D. Conversion to frank progressive disease, clinical progression and again, capital or a curve in the lower right now. You see it's about two years. So it really gives us a sense of the timing here and how we can counsel our patients if we're following M. R. D. We can kind of follow along and see, you know, when they do convert we can estimate maybe it'll take about two more years until they actually have clinical progression. So I personally find that to be helpful in kind of guiding patients about their prognosis. And I think the other thing that's that's emerged from this analysis that's helpful is looking at which of the patients that actually have a higher risk of faster M. R. D. Recurrence and faster progressive disease. And for the first time they've defined these factors. No major surprises here. You know, these are some of the high risk factors we already know about from CLL. So if you have the least in 17 P, if you have more genomic complexity and if you have a mutated I. G H. V. You're more likely to develop a faster conversion reconversion to MRT detect ability and a faster progressive disease. After time limited veneta clocks for talks map. So it seems a little obvious but this is the first time this has actually been shown with data and so I think it's helpful to understand that. And then just a little more information that they presented about the doubling rates of M. R. D. And the two arms. Which was interesting. Won't go into too much detail here. But one of the other things I wanted to highlight was just the last point about 16 patients now having been retreated with veneta clocks for talks a mob and having a subsequent M. R. D. Assessment. And you know the median PFS here is about 45 months. About 70% of the patients really respond to Veneta clocks a second time. So it does suggest that re treatment with the net clocks is going to be feasible but numbers are small. We need we need some more data there to feel more comfortable with that. I mentioned the captivate study in the front line setting, Britain plus fanatic locks and this is the relapsed refractory counterpart of that study. The clarity study which we've also seen presented and published previously. Uh This included high risk patients but really did not include any patients who are opposed to Bruno proposed fanatic lax. Again this is sort of an more historical population of post chemo immunotherapy only patients. Uh But one of the things that's unique about this approach and the clarity study is that rather than a fixed duration of therapy for a certain amount of time, they actually individualize the length of therapy for each patient depending on how long it took them to achieve undetectable M. R. D. With the rationale really being if it takes a longer time to get to undetectable M. R. D. Then you probably need more therapy to really get a deep remission that will be durable. So it took only six months to get to undetectable M. R. D. You only do another six months of Britain of veneta clocks. But if it took you a year you do another year. If it took you two years you do another two years of therapy etcetera. So with this scheme they recruited 54 patients, median age of 60 for relatively high risk population including about 20% deletion 17 p. medium of one prior line of therapy. And you can see the response rates now with longer follow up look great, 90% overall response rate but a very impressive close to 70% cr rate. Uh and then if you add in the C. R. I patients it's almost 80% of patients achieving a cr and the Kaplan meier curves to me look really outstanding here remember this is a relapse refractory cielo population and you're seeing a three year PFS of 96% the lower left. They did some interesting work around the M. R. D. Clonal dynamics and found that patients who had a faster achievement of undetectable MRG within the first two months were more likely to later on have a cr and to have a longer PFS. And the toxicity profile here does look generally favorable. This was again a relatively younger population. Again, you do see some of the typical eighties with with a broad nib in terms of a fib and and some bleeding events. But I'd say overall this was well tolerated interestingly. They did have in this update to covid 19 cases in patients in the study. But fortunately both both patients did well and were discharged from the hospital. So I think this is clearly an active regimen and it's going to be one that you know will will be utilized I think, particularly the front line setting. I think one of the challenges for this study and the relapse setting is that many patients these days are getting a brutal have already in the front line setting or they're getting veneta clocks abilities mob. So this dataset doesn't really apply to them. Uh And because so many patients have been receiving B. T. K. Inhibitor monotherapy, we've been very interested in Dana Farber at developing novel strategies and the relapse setting for that group. And so john Crombie presented an update from our dualism plus fanatic lacks trial, which really is targeted primarily at these patients who have received a B. T. K inhibitor in their initial line of therapy. Uh And so this is a phase one to study. Remember double is, it is a delta gamma P three Canada snippet are also an oral agent approved for relapse Cll. And here we gave it in combination with Panetta clocks for a one year time limited therapy and at the end of the year of patients still have detectable M. R. D. They can get additional veneta clocks uh if they don't they can uh stop therapy so they can go back into into observation mode and and be observed and so relatively early days with the study. But we presented data on 19 patients median age of 69 this was a very high risk population, about 40% with tp 53 aberrant disease. All but one of the patients had mutated I. G. H. V medium of three prior lines of therapy and about 65% or so had a prior B. T. K. Inhibitor. And about a quarter of patients had actually progressed well on the BDK inhibitor just prior to coming on study. So this this is the toxicity profile here with the p africanus emitters. We do tend to see more toxicities than we're accustomed to seeing with B T. K animators. And that's borne out in our dataset as well. You can see most of these events are grade 12 but we did see a fair amount of diarrhea, grade two in a few cases of grade three, we saw some rash and some infections. The neutropenia rates were high with this regimen, 78% in total, but about 68%, grade three or higher. So many of these patients did require growth factors support. So this regimen did did take some active management to be able to keep patients on treatment. But the payoff really has been in the efficacy so far. So, despite the fact that this is uh including many patients with police and 17 P and poster broad nib bi cycle 13 and 12 patients who have made it to that point so far, we've seen 58% cr rate. And all these patients have also had undetectable MRG in the bone marrow. On the right side, you can see the swimmer plot. So this had to phase one component with lower doses of veneta clocks initially. So we saw shorter responses in that 100 mg veneta clocks cohort. But as soon as we got up to 200 now 400 mg of the veneta clocks, you can see all those arrows are pointing to the right. So all these are patients still on active therapy. The red bars there represent patients who collectively have discontinued the treatment because they're in an undetectable M. R. D. ST uh And so several of these patients have now been off therapy without any evidence of remission. And notably all four patients who had progressed on B. T. K. Members have responded to this treatment and that study is ongoing. So, if you have relapsed patients who may be eligible, please do think about the trial. Speaking of P three kind exhibitors, I wanted to touch on the Unity CLL study. So this is looking at different P africanus inhibitor embolism, which is a delta specific inhibitor that's not yet FDA approved but is in these registration in phase three trials. In this study, it's combined with a new CD 20 antibody that's also investigational you Blue tux, a mob, so called you to regimen which was compared to abilities McLaren Diesel. You can see about 400 patients were randomized, 1 to 1 to the U two regimen, which is a continuous therapy versus the time limited six months of abilities made clear in brazil, the primary endpoint of PFS, A little bit of an unusual study because it included both front line and relapse patients. There was obviously a stratification for that. You can see the patient characteristics on the right median age in the late sixties, uh fair number of high risk patients uh and in the relapse population, a median of two prior lines of therapy in the U. Two arm. And this did include some patients who are post Bt Canada. So the top left, you can see the PFS, which is the primary endpoint. So did favor the U two regimen, I think most easy to interpret as the top right table where you can break this down by treatment. I even relapsed refractory. So, median PFS of about three little over three years in the Youtube regimen in the treatment naive group, only a year and a half or so in the relapsed refractory population. But certainly this is an active regimen. And I think, you know, we're most curious about the profile of P. Africanus inhibitors. And you can see here that although you see a fair number of grade one to events with you to, for example, diarrhea, nausea. The rates of grade three or higher toxicities were lower than when we were accustomed to seeing with other pr three kindness numbers, I think, particularly in the front line setting. Uh you know, there we've it's really been prohibitive to use P three Canada senators, the ones that are already approved. And here, I think it's good proof of principle that um melissa may be feasible to use in the frontline population. This could be one of the more practice changing abstracts from ash this year because this is hopefully going to lead to a label for amber. Listen, with your buttocks, Marvin Cll later this year. So the B T. K inhibitor floodgates have now opened. So we've talked already about the irreversible covalin inhibitors Uprooting of a caliber alexander Britain in. But there's also a next generation of B T K inhibitors that are reversible and non co violent Air Q 531 which was acquired by Merck and lock so three or five from lily. And so there's I think really going to be an important role for these drugs. You can see here that in terms of reasons for Britain of discontinuation from for for prospective studies, that gray bar coming up in the middle is CLL disease progression. So as you get out sort of 3 to 4 years on a broad nib really do start to see Cll progressing in a fair number of patients. And on the right that pie chart suggests that about 70 to 80% of these patients will have B. T. K mutations. Typically the C. Four A one S mutation which causes resistance to a brunette and a calibrated and zanna burning. Some of them also have PLC gamma two mutations. And so we saw some great data at the ash meeting updating the locks 0305 Phase 12 Bruins study. And this is a study that we've participated in Dana Farber and put quite a few patients on. So we have good experience with this drug. Initially they presented just the safety data here for all be some malignancies which was 323 patients. That then they also broke down the efficacy data for the cll population of 170 patients. And these patients were a median age of 69 years and many of these patients had had prior B. T. K inhibitors. Uh and you can see that here, 86% prior B. T. K inhibitor. And this is quite a high risk population as well, with about 30% having tP 53 aberrant disease. So in this whole safety population, you see very few grade 34 A. S. You don't see very much a fib hypertension bleeding. Some of the things that we're accustomed to seeing with Bt canisters. This is a very specific B. T. K inhibitors. So that may help with the talks profile. And yet you're seeing excellent efficacy and particularly in this post B. T. K population, about a 60% overall response rate. But, you know, the follow ups very short as you see from the swimmer plot in the lower left. So in the patients who are now already out to 10 months on therapy, the overall response rate is 86% and you can see the PFS curve looks quite favorable so far. So this is an early data set. It certainly looks promising and I think importantly at the very bottom of this forest plot you can see that irrespective of B. T. K mutation status. This is a very active drug. So it could be a good option for patients, certainly with the TK mutation on a B T. K inhibitor, but potentially in the future, even for patients who are B T. K inhibitor naive. The last part here, I just want to touch briefly on car T cell data in CLL. This is just a review of some prior studies of Cartier and CLL, it's been a tougher modality to develop I think as compared with say Dl BCL because we know that there's this inherent immune dysfunction in CLL. We're trying to rely on T cells that are often dysfunctional from CLL patients to affect an immune response. And so the cr rates from prior studies were sort of all over the place but in general about 20 to 40%. And so this ash meeting we saw two important updates for lisa sell this is the transcend Cielo for study of jake are 17. So these were relapse CLL patients who in general had very high risk disease about 83% had at least one high risk feature. Most of these patients were posed to brute nib. Some of them were also post veneta clacks. I won't get into all the nitty gritty of this trial design but it was pretty standard approach for car T. Cell therapy. 22 patients. And so these are the data for lisa sell monotherapy which we've we've seen previously. Uh The CR rate here is in the range of about 45% and the PFS curves I think, look look reasonable there, the median PFS is 13 months but the patients who do achieve CR can have somewhat durable responses. The follow up still relatively short. Uh And the rates of CRS and neurologic events are relatively low. So this looks promising. But I think what was even more interesting was we saw for the first time data from the brutal combination arm in this trial. So lisa sell plus a brunette 19 patients treated. Uh and they were given a brute nib concurrently with the car T cell approach. And you know, obviously a little hard to compare between the different chords. The populations are slightly different. But you do see in the top left here in all patients is 63% rate of cR so a hint that maybe there there's a bit better efficacy when you add in the broad nib and then the lower left. You see the CRS rates are quite low. Only one patient with grade three or higher CRS only three patients with Read three or higher neurologic events. Maybe a hint that Britain is helping to mitigate toxicity. I think it's it's a little hard to know. But certainly this looks like a promising start especially with looking at M. R. D. Undetectable. Itty rates were about 80% and this very heavily pre treated population. So to wrap up here, conclusions from cll at ash 2020 in the front line setting, I showed you the updated data from CLL 14 to me the takeaways from that where that 74% PFS rated four years as well as some of that interesting data about colonial dynamics and how M. R. D. May improve our understanding of the outcomes of these patients. We saw the first time we saw the presentation of captivate M. R. D. Cohort which is a burden of veneta clocks, highly effective frontline therapy. I think it's a good proof of principle. We can begin to think about using M. R. D. To guide therapy duration. Uh this is not yet a standard of care but getting there soon probably. We saw updated data from our ongoing abo study that's I think highly active and well tolerated including for the high risk patients. And please do keep that study in mind for high risk patients that you have. And then the sequoia update showing that zanna Britain have also has a favorable safety profile and is quite active for frontline 17 PCL The relapse setting, the five year Murano data have now defined a median PFS of 53.6 months and identified some risk factors for faster progression after stopping therapy, as you see here clarity study of a brunette plus fanatic locks is clearly effective in the post chemo setting and gets to this idea of individualized MRT therapy, which I think is really interesting, at least in the trial setting for the post B T. K inhibitor population. We updated our data from our ongoing study of dualism plus fanatic lax and although we did see some toxicities, this was a very potent, time limited combination. It was quite active should you data from the youtube uh, study the unity study which is a PS three can be spaced regimen that's quite, quite active and and feasible for both front line and relapse CLL and I think will likely be registered later this year. We saw exciting data from the ruins study of Luxor 305 the newer BDK and editor that seems to be both active and well tolerated, irrespective of B. T. K. Mutation status. And then finally I showed you the data on lisa's cell with or without Uprooting him. And I do think this continues to be promising. And I'm hopeful that eventually will get an approved car to sell product for our CLL patients with that. I'll stop and happy to take any questions. All right. Thanks man. It was really a fantastic talk with some amazing data. This field has changed dramatically over the past few years so we have some questions. Um I think the first one is uh what is the role of M. R. D. Testing and in patients who are not on clinical trials? How do you do it? Do you do it? Um Which tests? Yeah. So this is you know an evolving area. I I was not routinely testing MRT outside of the trial setting until fairly recently. I think with some of the data that I showed you here there's a lot of value in terms of predicting for example progression free survival and probably overall survival with veneta clocks based regimens. So although it's not sort of specifically changing the duration of therapy yet I have sort of gotten in the habit of checking it. I usually would would use flow based M. R. D. We use a send out test, we send it to Mayo lab so as long as you set up an account with them it's pretty easy to send. Uh There is also now adaptive Kelowna seek. The only thing with that is you have to remember to get an I. D. Sample before the patient starts. So you have some tumor cell to sequence. Uh And then you can check it later. So we started doing that as well. Another scenario where that can be helpful is like patient who's maybe eight months, nine months into veneta clocks abilities amount but running into a lot of toxicity. So you check out our D. And if they're already undetectable, maybe you feel more comfortable backing off on the dose or stopping therapy. Whereas if they still have detectable MRG maybe you really try to push them to get through with supportive care to try to maximize response. Great thank you. Um So question about patients who are on a brute nip uh You know now we have these uh calibrated and you show data for santa Bruton. It being significantly better tolerated. When do you think about switching? So here's a question about someone who gets minor piece taxes. The patient finds that very annoying. When would you switch someone? Um would you ever add something, you know, would you ever add veneta clacks in order to give time limited therapy to someone who's doing well on a brunette? Yeah, so first, you know, for patients who are doing very well on a brutal and I would not switch them to one of the new B. T. K inhibitors, you know, the situation you bring up here at pissed axis is sort of in that gray zone where you know, depending on how annoying it is to the patient, you could think about switching, although I would say that leading is not one of the biggest differentiators between these drugs. So that's probably a patient, I would continue on a brood in it. But if I had a patient who ran into atrial fibrillation on a broad nib and I wanted to keep them on a B. T. K. Inhibitor drug. That's a scenario where I probably would switch them to a calibration. IB you know, if I had a patient who already had cardiovascular comorbidities kind of going into treatment, I might start with a caliber numbers and a brunette. And that that scenario uh there's been some data presented on adding in veneta clocks to try to deepen response and get patients offer Brittany. But I would not consider that to be a standard of care. We have a study open at Dana Farber right now adding in the Petri candy senator copan Lissa these patients on a brunette to try to get them off off therapy and I think that's a very promising approach as well. So if you do have patients that study is open and recruiting now will be very, very interested in treating them. And then maybe one last question. Can you comment on the use of G. CSF prophylactically? And if patients get neutropenia on veneta clocks that have been A to Z mob and with regard to that particular regimen, do you expect similar response rates and patients with big nodal enlargement compared to people who have more of a Olympus psychosis type presentation? Yeah. So in terms of the first part of growth factors support I tend to use it fairly liberally during veneta clocks open. It is a mob veneta clocks is definitely associated with neutropenia. It's an on target effect of the drug open. A twosome have also causes that. So you see grade 34 neutropenia and probably 50 to 60% of patients on veneta clocks open it to the map. And so typically as the N. C. Gets less than 1000 I will use growth factor. And typically that then allows me to continue the regimen without interruption without dose reduction. Uh I'll give Neulasta or you know other long acting growth factors and and you know typically it's not every two weeks you know maybe giving it once in a month or two later you need to give another shot not for all patients. So so that is something that I like to do to be able to keep patients on the therapy. Um Sorry I'm forgetting. The second part of the question was was the response to that combination comparing patients who have more bulky and novel right martin psychosis. Thanks. Sorry. So uh we've studied that in the veneta clocks monotherapy setting where actually it did seem like veneta clocks was not quite as effective if you started it in patients with bulky disease in terms of eventually achieving a cr uh that has not really been uh an effect in the veneto flexibility is a map combination in the front line setting. So I do tend to think of it as being sort of equivalent to B t. K neighbors, at least based on the data we have so far. I think both of b t k, an editor or genetic flexibility is a map is a great option even in patients with with bulky lymph node disease. All right, thanks so much. That was really an outstanding talk. Published Created by
