Dr. Anthony Mato explains novel therapeutics in Chronic Lymphocytic Leukemia (CLL). Dr. Mato reviews different trials and provides effective frontline therapy options.
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it is now my pleasure to introduce my friend Dr Anthony Made a who is currently the director of the CLL program at Memorial Sloan Kettering Cancer Center. He is very well known in his field, especially with regard to novel therapeutics and the real world implementation of novel therapeutics in CLL today. Who will be speaking on the topic? Modern treatment options for CLL Uh, we are very fortunate for him to come back to this conference to give us a state of the art presentation on CLL, and I really do appreciate him taking the time out of his schedule today to give us this lecture. Please do reserve your questions for afterwards. During the panel discussion, they will be address and please type them into the ask a question function in the chat box during his presentation. And Hi, my name is Anthony motto from Memorial Sloan Kettering Cancer Center, um, the director of the CLL program, and today I'd like to present emerging agents and combinations and chronicle Pacific leukemia. These are my disclosures. I'd like to start with taking a historical look at the tremendous progress that's happened over several years, really decades and the management of patients with chronic lymphocytic leukemia, starting with the development of single agent chemotherapy in the 19 fifties and 19 sixties, transitioning to combinations of chemotherapy in the 19 eighties and then, finally, the development of chemo immunotherapy combinations in the 19 nineties and early two thousands. More recently, this slide highlights the tremendous progress that's happened over the last several years, where several targeted agents have been approved for patients both in the front line. And relax your factory settings, which have demonstrated improvements in quality of life, deepened response rates, improvements and progression free survival, as well as improvements in overall survival. Today we're talking about the forefront of development and the management of patients with CLL, with a focus on novel agents that target things like the macro environment, the cell receptors signaling as well as harnessing new cell surface targets and the cell death machinery. The way I've organized this task is the following. To begin with, we'll talk about advances that are the next generation of therapies for 2021 beyond in the front line setting, including the CLL 14 trial, where we're looking updated data for the combination event with amenities a map. The Captivate Trial, which is an Mardi driven approach looking at the combination of vibrant and plus phonetic, lacks both Avio involve in our two new regimens. Looking at the combination of a second generation B T p p t k inhibitor with Vanna Vanna, Choose a mob and how those data are looking The Sequoia Update on the Dell 17 p patient population in the front line setting treated with Sandy Britain Um and then we'll delve into the relapse. Refractory setting, looking at the Murano data set and updated data for Ven plus rituximab, a new kid on the block three cape paste regimen called YouTube. Well, look at next generation BTK inhibitors that are non covalin Oxo 305 car T cells. The list of Captain DJing with or without Britain, Um, and then the d TRM combination specifically for patients with Richter transformation. I'd like to begin with the topic of treatment naive chronic lymphocytic leukemia and delve into the CLL 14 data set. As many of you know, CLL 14 is a study that was conducted by the German CLL Study Group. This is a 1 to 1 randomization looking at the fixed duration combination event with amenities a mob for one year as opposed to clarify So with a minute choose amount for one year. The antibody and each arm is given for six months. The oral therapy is given for 12 months. This is an older, more frail patient population, with the primary endpoint being progression free survival key secondary endpoints included Response. Margie and overall survival. This is the take home from the clinical trial. Here we see updated data with immediate observation time of 39.6 months. The then open was superior in terms of progression free survival. You can see the median is not reached for the chlorine vessel opened its 35.6 months and the three year progression. Free survival was really different. 81.9% versus 49.5% with a hazard ratio of 0.31 Some of the more interesting data to come out of this data set at the more recent ash meeting have allowed us a window into M R D patterns over time. So M R D is not necessarily a static thing, and one of the things that came from this data set were we wanted to look at patterns of Mardi, whether it was increasing or decreasing at the end of end at the end or near the end of therapy. And about half the patients had positive growth in m r D towards the end of therapy, really suggesting that they probably would not have benefited from additional genetic lax. But there was also about half of patients where the M r D um, negative growth was decreasing or deepening, with time suggesting that there are subsets of patients who may benefit from additional M R D and then, of course, or additional Veneta clacks. And of course, you can see here the proportion of patients who are M R D detectable or undetectable by the end of therapy is 74% versus 32%. So Van is truly a very active agent in terms of inducing deep permissions. Okay, we also have updated data presented on this combination With four year follow up, you can see again the data looking at the median PFS not being reached versus 36.4 months. The four year PFS is 74% versus 35.4%. Those are statistically significantly different, as well as the time to next treatment. At four years. For the van O B. It's 81.8% versus 59 9% and also the number of patients who actually require a next anti leukemia therapy is quite different between the arms, really suggesting that the rate of progression is different between the arms, Um, and that not all progressions are the same. And certainly it seems that the vent progressions are requiring, um, over this time period less of a need to start a new leukemia, a new CLL based therapy. So the summary for this presentation is that this analysis demonstrates that individual clonal growth rates can be used to estimate M r D doubling after a fixed duration treatment. Clonal growth was slower after Benji, as compared to chlorine BCG and in a subset of N G treated patients. No clonal growth was measurable during the observation, which is an intriguing observation. Maybe in the future will learn if there's a tail on the curve. The next study I want to highlight in terms of the forefront of CLL is the captivate trial, which was also recently presented at the ash meeting. This is an Mardi driven approach, looking at the combination of vibration and plus Veneta clocks in the front line setting. Patients are 70 or younger. Treatment, naive, patient, population. Everybody gets a three month leading with the brute name, followed by a 12 month combination of vibration and plus phonetic lax. And then there are two. Randomization is based on Mardi status in month 15, either randomization for for patients or Mardi Undetectable Randomization to placebo vs I brewed in him for patients who are M R D, not confirmed or or detectable by Britain and versus continued combination of vibration and plus Veneta clacks, with the primary endpoint being a little bit controversial in terms of the amount of follow up, one year disease free survival and confirmed undetectable MRT patients. And here you can see the Kaplan Meier curves for a brutal and versus placebo. No statistically significant difference. One year DFC rate for placebo was 95% versus 100% so this provides some reassurance that 1 may consider stopping the I brought nip after the 15 months of the iPods. The combination as prescribed in this regimen. Um, the other thing that we learned is that the other randomization for the M R D detectable patients provided some insight in terms of the fact that that Mardi did not deepen with the eye Britain and mono therapy alone, but did continue to deepen over time with a combination of I plus v beyond month 15. This is a complicated slide, but gives us a window gives us a window into the profile for the combination. Nothing really unexpected. Um here, except to say the rates of atrial fibrillation were relatively low. The discontinuation rates were still relatively low for the combination, but no new signals for the combination. Certainly, it appeared to be better tolerated in the multi center study than it did in the M. D. Anderson cohort, which was a single center experience. The summary here is that the 30 month PFS rates across all arms compared favorably to other frontline fixed duration regimens thinks a little bit of a bit of a stretch because certainly it's an apples to oranges comparison. Eighties decreased after the first six months on I plus V. No new safety signals emerged over time and that this is an oral, chemotherapy free fixed duration regimen that is Mardi driven. So that's certainly novel. I also wanted to now delve into the novel novel novel combinations that have been presented in several meetings over the last couple of years, mostly because these are also windows into M R D driven approaches. This is the Botvin regimen. This is a previously untreated patient population. Looking at the combination of Zan you brute nib with phonetic lax and I'm gonna choose a mob, you can see the schema. There's a lead in of the san you open, followed by introduction of Veneta clacks. But the key take home from this study is that patients have sequential MRG assessments in the blood and then marrow if confirmed in the blood, to allow patients to just continue this regimen in the setting up response plus m r D undetectable disease, 39 patients participated. You can see the best, um, undetectable. M R D rates were 91.9% in the blood, 89.2% in the marrow and 100% overall response rate. And then there was 89% of patients had achieved undetectable disease in both the blood and the marrow and stop therapy after a median of 10 months. Quite impressive. This is illustrated on the swimmers plot, where you can see only one progressive event out of the 39 listed so far. And the blue bar is the treatment free period Treatment free duration period, which is also now starting to become longer than the actual exposure to the drugs. These drugs are well tolerated in combination, nothing unexpected from the profile Most common adverse events for human to logic. Matt David's at the Dana Farber has taken a similar approach, creating the Avio regimen, which is a calibrated and Veneta klaxon amenities. A map frontline, slightly different design. There's an a calla lead in, followed by Introduction of Obi, followed by the triple combination. And patients have a cycle 16 assessment for patients who are in C, R and M R D. Undetectable at that time point, they can stop. Otherwise, they can continue on therapy and have additional opportunity to stop. Based on response. 44 patients have participated in this trial. Be a profile again highlights how well tolerated the combination was very limited. A s of special interest you can see hypertension, 11% a fib. One event TLS to grade three events actually related to open and not Veneta. Clacks and I are ours were seen in 25% with most being grade 12 You can see here the response rate data for this, um, study was quite high, essentially 100%. And there was a large number of patients who participated to a TP 53 irreverent disease who also had a pretty spectacular response rate. So the summary was that HBO demonstrated efficacy and a favorable safety profile in patients with high risk treatment. Naive cll. No TLS due to ven was observed. There was TLS due to open, which is a great reminder that that drug is not without risk. A cruel to a TP 53 aberrant cohort is ongoing, so that will be very important data. And there's a phase three trial of Avio versus a V versus chemo immunotherapy in the front line setting, which is currently accruing. The last trial I'll highlight in the front line is the Phase three Sequoia trial of Sanya Brewpub. And you might say, Well, what's so unique about a front line b T k Mono therapy trial. What's unique about it is the patient population. These are patients, all of whom had a deletion. 17 p 109 patients. And while we talk about a brute, Navarrete Caliban, standards of Care and poor risk featured patients like Dell 17 p in the front line setting. There are really no large multi center data sets that exist in with those agents, but there is one with Daniel Britain, which is why I'm considering this trial to be state of the art. 109 patients. Overall response rate. 94.5% PFS. His excellent 18 month PFS was 19.6%. 18 month overall survival was 95.4%. So really demonstrating the efficacy of the class of B T K inhibitors, specifically zanna, broad nib and the durability of response. No major signals again that we would expect here. The drug was well tolerated until the summary for this study was that Sanya mono therapy for patients with Dell 17 p treatment naive CLL was well tolerated, with low rates of discontinuation and high response rate demonstrated. PFS appeared to be preserved in patients with a mutated I G H I V and complex Carry a type. Next, I'd like to delve into the world and relapse refractory cll and again, we'll start with Veneta Clocks based therapy. This is the Murano trial, which was a 1 to 1 randomization of the combination of ven are with are being re toxin map given for 24 months, six months of antibody 24 months of oral therapy versus B R, which has been a muscle injury toxin map given for six months. The primary endpoint was investigator assessed PFS. The secondary endpoint was rates of clearance of M, R and D. And so this is two fixed duration combinations 24 months worth of therapy versus six months, with the primary endpoint being PFS. We have updated data now with a five year analysis, and here you can see now we have a median for men are, which is 53.6 months and a median for BR, which was, um, 17 months so certainly statistically significantly different in terms of PFS Also overall survival. At 16 months, you can see it's 82.62 0.2%. What I thought was really interesting from this data set was that we now have a window into time periods from end of therapy. So end of 24 months to M R D conversion meeting going from negative to or undetectable to detectable. That medium was 19.4 months, and then the time from Mardi conversion to actual progression of disease was 25 2 months. No new safety signals were observed here. Largely Humaita logic Associated um toxicities. And also we have new insight into the M R D doubling time. Post therapy, which does appear to be somewhat different between the regimens and does appear to be somewhat affected by the presence of poor risk features like a dilution 17 p or complex. Carry a type or I G H B I mutated disease. So it's not only about depth of remission, it's about the regimen. And it's also about the biological features which predict the rate of conversion from undetectable to detectable disease in summer event are displayed. Adorable Response and PFS and OS advantage over BR Mardi. Doubling rates accelerated by poor baseline characteristics and Mardi status at the end of therapy predicts for outcomes Well. Now let's delve back into the world of P I three k inhibitors, which we haven't really talked a lot about over the last couple of years. And look at the Unity trial, which is a combination of, um, Melissa and politics. Um um, unique design in both the front line and relapse refractory settings with the Comparator in both settings being the CLL 11 regimen, which is geek Laura Benson. Over 400 patients participated in this trial. They were comparable in terms of baseline calculations, a baseline characteristics and the primary endpoint was progression free survival for the entire cohort, both front line and relapse refractory. You can see here the Kaplan Meier curves, the green is the YouTube combo was superior versus the open, clear and Brazil combo median. PFS was reached in both arms, 31.9 versus 17.9 months to Europe. PFS was 60.8 versus 40.4 months, and there was a significant difference in terms of oh, are are being 83.3 versus 68.7. Of course, when you're thinking about P I three k inhibitors, we have no doubt about the target or the activity, but also we need to look at the A e profile because it's somewhat distinct from the other targeted agents. Here we can focus on P I three k specific A s and C A L T elevation at 17% all grade S T 13 6% colitis, 49% infectious colitis, 5% pneumonitis to 9% rash, 12. 6% an opportunistic 14.1%. And some are a YouTube demonstrated superior. PFS to G. Karam, Brazil, and patients with CLL both in the front line and relapsing factory settings. YouTube displayed consistent benefits irrespective of prior treatment, status and unity. CLL is the first phase three trial of a P three k inhibitor combination in treatment. Naive to show feasibility of this approach well, we've talked about the Covalin B T k inhibitors or the irreversible B T K inhibitors, including I brute nib a calibration Evans on you, Brute nim. I now want to delve into data that our group presented on lock So 305 which is the next generation highly selective non covalin B t K inhibitor. And this is in relapse refractory cll. Of course, the major issue with the B t K inhibitors that are approved. To date, our discontinuation is either due to toxicity or resistance, with discontinuation rates ranging between 41 to 54% at five years from clinical trials. So certainly most patients who started on a B t K inhibitor as a monotherapy will require another therapy. Five years later, the most common uh mechanism for acquired resistance, or BT computations seen here in about 56% of patients, Lot three or five is a highly potent, selective, non covalin B T K inhibitor. You can see the kingdom selectivity. It's about 300 more fold selective for B t k versus other kindnesses. And due to this new mechanism of action, the reversible binding mode, it's not impacted by a high intrinsic creative dtk inhibitor turnover. And it's far Michael Logic Properties allow sustained B, T K and ambition throughout the dozing interval, so it's designed to be a better be TK inhibitor. We presented data on 170 CLL patients. Media number of prior therapies was 34 If you look at just the B t k inhibitor exposed patients, which represented 86%. This is also a fairly high risk patient population, as you can see under the baseline Molecular characteristics. And 27% of patients who have data available did have assist for anyone. Mutant, of course, with a Phase one trial. It's not only the activity, but more about the safety profile. And you can see here for all 323 patients, which this includes lymphoma patients who participated in the trial. This drug was incredibly well tolerated. Uh, just a couple of examples, I'll note. Only 5% are through algebra, less than 1% Grade three hemorrhage. Um, overall, 5% hypertension and less than 1% a February flutter. No DLT s were reported. The MTD was not reached. The discontinuation rate due to a E was 1.5% and the phase two dose was selected at 200 mg once per day. In terms of activity, here is the waterfall plot. Blue bars or B T K inhibitor exposed cll patients stratified by reason for discontinuation. Red hash marks are prior BCL two inhibitor. That's Panetta. Clacks Stars are cysts for anyone. Mutant disease, universal activity across the board and we can see that the overall response rate was 63% 62% in the B t K inhibitor exposed patients. But over time, in that subset of patients who had longer follow up, we see that that rose from 63% to 86% in patients for whom we've had 10 or more months. Follow up the swimmers plot shows the durability of response. Here, the median follow up in six months. 94% of responding patients are ongoing and in response, with only five discontinuation is either due to P D and four or one who electively discontinued to go to stem cell transplant. And this figure is quite helpful because you can see in certain high risk groups like those who failed every prior therapy, including chemo CD 20 b t k BCL two MP three k. That that response is maintained has is the response in patients who had a prior B T K inhibitor and discontinued um, regardless of progression or toxicity, or when you look at wild type versus his 41 mutant status. Keeping in mind the follow up is still short. The duration of response and the PFS looked quite encouraging. Next, I'll delve into the world of car T cells directed against CD 19. In this slide is a nice summary of all of the data available to date looking at Cartier and CLL. And while this these agents have a lot of fanfare in terms of their activity and potential to cure patients, you can see that the number of patients in each individual study is quite small. There are two updated data sets that I think are clinically relevant. Presented at the ash meeting one by Tanya Siddiqui, which was in a B T K inhibitor treated patient population almost all exposed to prior phonetic lacks as well where she looked at. Listen, Captain Jean, um, as a mono therapy or or uh, without not being in combination in this high risk patient population, you can see the O. R. Was 82%. 27% of patients had a deepening of response. At 12 months, 50% of patients were in response, and only two of these responders progressed beyond 12 months. So the summary here was an O. R. R of 82% to see our rate of 68% median PFS of 13 months and no real significant news. Um, e signals beyond what we would expect. But four of six progression events were due to Richter's transformation bill Weirdo took a different approach. I looked at the same product in combination with my brooding, um, and a less heavily pre treated patient population of 19 patients. And here we see, um, the approaches to combine the car with the I brought in to take advantage of the fact that I brought in and may have t cell activating properties. Um, in this relatively small patient population, all responders achieved a response by day 30 among 18 patients with six or more months follow up, 89% maintained and improved response. And so the summary here was that list. So plus, I brought in. It was well tolerated, with low rates of high CRS, or neuro toxicity, an o. R. R of 95% a CR rate of 63% with marrow negative and approximately 80%. Yeah. Finally, I'll delve into the world of Richter's transformation, which is the dreaded complication of CLL, which occurs in about 5 to 7% of patients where patients can transform to either a deal BCL or Hodgkins variant. It's associated with a dismal survival, who was first described in 1928 and there have been some advances presented over the last few years. This is a study that I presented at the ash meeting. Look at looking at an oral daily triple combination of a B T K inhibitor. Enter inhibitor, an image for the treatment of relapse refractory Richter's transformation. This concept is called the DRM concept, which essentially starts with a a new Covalin B T K inhibitor and then through in vitro and in vivo screening procedures, the development of a triple combination for human trials. The best combination was this B T K inhibitor, with every Lima's and Pamela to mind given at low doses to synergistically kill malignant B cells. And this is an optimized, once daily triple combo of those agents that I've already mentioned hitting these three individual pathways with the hope of obtaining a synthetically fallacy like effect. This is a multi stage trial where Stage one patients got a B t k inhibitor, followed by Stage two the D T r M 12 b t k inhibitor with every Lima's and then Stage three, the triple combination given to patients. It's a very, very heavily pre treated patient population. Richter's. We saw a median of three prior therapies. Most patients had what we would have expected, including CD 20 anybody's chemotherapy and prior PDK inhibitors. The triple combination was well tolerated. Neutropenia grade three or four or thrombosis a DPD a grade three or four were the most common A es but were largely, um, manageable during the one week um, treatment for interval, which occurred on every cycle. These were 28 day cycles with a break between day 21 day 28 or with growth factors, support and the recommended phase two dose here was DRM. 1200 mg ever leave us at five and Pomelo pomelo to meet at 2 mg once per day. The overall response rate in Richter's was 46%. The waterfall plot, um, here with the blue bars represents the Richters transformation, certainly not universally active, but in um but we can see that nine of 21 patients on this study, which included some DL BCL, had a greater than 50% reduction in lymph nodes the top part of the swimmer shows the victors cohort, where we can see that responses were durable in some patients. And then we focused in on the Richters cohort just to show in the responders how heavily pre treated these patients were, what they had received before and the duration of response available to date at the time of the presentation. And then, of course, a picture is worth 1000 words. This is a pet CT or a pet rather of a patient who is treated with this combination at Baseline versus Cycle five. And you can see here that the patient had a complete metabolic response. So in conclusion, Cielo 14, which is then open, provide adorable benefit for most patients for your PFS with 74%. And Clinical Dynamics and M R d improve our understanding of outcomes. In the captivate trial, which was marred, driven by plus V was highly effective front line therapy Mardi can be used to guide therapy. We saw two new triple combinations which, unlike the data that we had from some of the older I've written based ones, were truly M R D driven, highly active, well tolerated and then in the Sequoia Update, Sanya Bruton, um, has a favorable safety profile in the 17 p patient population and the relapse refractory setting. We saw updated data from Murano, which now gives us a medium for Ben. Plus are we also saw the not only was it the depth of remission but the prognostic features at the start of the regimen predicted for the rate of progression and the M R D conversion rate, we saw a new P three k inhibitor in a randomized setting frontline particularly interesting as compared to open plus clear and Brazil. We saw lots 0305 which is the non violent B T K inhibitor being active and well tolerated, both in B t K inhibitor, wild type and mutant disease, a new triple combination for Richter's transformation being explored and then updated data for Car T as a monotherapy, the Lysol Captain Jean product or in combination with the brute nev. And then special thanks to Matthew David's for helping provide some of these slides and also special thanks to the meeting organizers and Maren Xavier for inviting me to give this talk. Thank you very much
