Update on key studies of acalabrutinib in the front-line setting

DR LOVE: Welcome to Oncology Today: Key Presentations on Chronic Lymphocytic Leukemia from the December 2022 ASH meeting. This is medical oncologist Dr Neil Love. For this program, I met with Dr John Allan from Weill Cornell Medicine to discuss a number of key presentations from the meeting, beginning with papers on first-line management utilizing BTK inhibitors. 

DR ALLAN: Hi, everyone, I’m John Allan. I am coming to you from Cornell here in New York City, where I am an Associate Professor of Medicine in our Lymphoma Department. I see patients with non-Hodgkin lymphomas and my research interest is in CLL, where the majority of the patients that I see have that disease state.

So we’re going to talk about today some ASH updates from the past ASH in December of 2022, and a smattering of abstracts and updates that I think are important to be aware of and to learn about and to understand. And then, obviously, we’ll have a discussion about how these important data sets might start to impact the management of our patients going forward.

So this is a Research To Practice ASH 2022 CLL Updates.

So, here, we’ll first go over the front-line studies that were done in treatment-naïve CLL, and look at, break it down in terms of some of the acalabrutinib-specific updates. And then there was a whole session on combination approaches with triplets and doublets. And now we’re actually starting to identify some risk factors with fixed duration approaches that might identify patients that have earlier relapses and we may be needing to think about differently as we go forward.

We’ll then, after several of those abstracts, we’ll move on into the relapsed setting where we’ll look at the big splash of ASH which was the late-breaking abstract with ALPINE, which was looking at zanubrutinib versus ibrutinib. And then we’ll see pirtobrutinib updates, which now is we’re getting good follow-up for these patients and really going to understand where does this drug have a role in CLL and how effective is it in these high-risk patients.

And then we’ll highlight a few novel therapeutics, particularly with BCL2 inhibitors. There were 2 that were showcased at ASH. Bispecifics. There was a few other compounds we can talk about. But in interest of time, we’ll cut it there and provide just those updates there.

So moving on into the front-line setting, here are the big acalabrutinib updates that are important to realize.

So John Byrd published 6-year follow-up of the initial 99 patients treated on the CLL001 study, which was a large, Phase I/II study, but these were the first initial 99 treatment-naïve patients received acalabrutinib. Now we have 6 years of follow-up, which is now very competitive against the 8 years of follow-up that we have with ibrutinib. And we’ll give some high level updates there.

And then we’ll move on into some updates from the ELEVATE-TN study with acalabrutinib, plus or minus obinutuzumab. And we’re seeing an interesting finding where PFS and outcomes and response rates, et cetera, may actually be improved by obinutuzumab. And the question is, who benefits? And who should we maximize these therapies for? This abstract is very helpful in identifying that and starting the first few steps in trying to understand and apply that to our patients.

And then Ryan Jacobs had a real-world comparison of time to next treatment. And we’ll see some data there, ibrutinib versus acalabrutinib. And I’ll give you some inputs and thoughts on that as well.

So here is the update from the longer-term follow-up from the initial 99 patients treated with acalabrutinib in the early Phase I/II study. And you can see here that at 7 years now, pretty much at this 7-year PFS, estimated PFS mark, there’s 87% of patients are progression-free. Now, this is historically better than what we’ve seen with BTK inhibitors from RESONATE-2, et cetera, and this is maybe even historically better that what we’ve seen in the ELEVATE-TN study, which is in treatment-naïve patients as well. But regardless, we’ve got long-term follow-up, from a decent number of patients, being treated uniformly with twice-a-day acalabrutinib. And we’re seeing very effective 7-year outcomes.

To put in perspective, ibrutinib at the 8-year mark with a median of about 7.5 years of follow-up, but patients up over 8 years of follow-up, that median PFS also has not been met at around 57%. And those patients are continuing to do well; a little under a half of them remain on drug.

So this is comparing very favorably. This is essentially a 6-year median follow-up. Some of these patients are out over 7 years. We’re seeing really good progression-free survival and comparing very historically well, if not more favorably, to what we saw with ibrutinib.

Now with that said, this is a small study. We need to see the ELEVATE study and we need to see some of these larger Phase III clinical trials to come through, but this is a nice benchmark. And I think gives us a lot of confidence in using this drug, whereas previously, ibrutinib had all the long-term data. We were still scratching and yearning for understanding what long-term with acala looked like. Now we have that. We previously saw 4-year data from this data set, now we’ve got this 6-year data. I think we’ve all feel very confident in the effectiveness of acalabrutinib and this data set helps that.

We see BTK inhibitor class effects. We do see in these treatment-naïve patients some arthralgias. We see diarrhea. Contusions. For the most part, they are low grade. You don’t see very much high Grade 3 or greater toxicity. But even though these drugs are more selective, we still have to deal with BTK inhibitor class effects. We still need to be monitoring for them, thinking about them. But fortunately, with these newer agents, second-generation agents like acalabrutinib, we are seeing less of these higher or more serious things like AFib and cardiovascular events.

So here, moving on, where Matt Davids presented some analyses on these subgroups on who should be benefiting from obinutuzumab. One thing, and I’ve been on record saying this in the early first years of the ELEVATE-TN, that I did not think that obinutuzumab with just 6 months of treatment would potentially impact some longer-term outcome.

What we’re seeing though, is that with each update, initially at 2 years, then at 4 years, and now at 5+ years, the patients in the treatment-naïve arms getting the acalabrutinib plus obinutuzumab, continue to have better PFS, progression-free survival, than those patients on acalabrutinib monotherapy. And clearly, both of those arms, acala arms, are much better than the chlorambucil/obinutuzumab arm.

And with each subsequent yearly update, we start to see that this progression-free survival continues to widen, and those patients with the obinutuzumab addition seem to be gaining some benefit.

Early on, it seemed like it was the lowest-risk patients benefiting. Now with 4- and 5-year follow-up, even the unmutated IGHV higher-risk patients seem to be benefiting. And this continues to widen over time.

At the most recent 5-year update, there was actually an overall survival benefit for acalabrutinib/obinutuzumab over chlorambucil/obinutuzumab, not over acalabrutinib. But the acalabrutinib and chlorambucil/obinutuzumab arms are actually tracking along rather similarly at this 5-year mark in terms of overall survival. So is it possible that we will see an overall survival benefit between the 2 acala arms remains to be seen, but I suppose it could happen.

For reasons for this, I’m not quite sure why these patients are doing so much better. It’s not necessarily completely clear, but this data set is starting to help us understand which patients that we should maybe think about adding anti-CD20 therapy to, particularly obinutuzumab to acalabrutinib.

The most impactful and valuable thing from this is that when you look the highest-risk patients, del(17p) and complex karyotype patients, so on the far left here and almost on the far right here, the second from the far right, you can see that they actually do not benefit from the anti-CD20 addition. And I think we were all maybe hopeful that, oh, the high-risk disease, we can add something on to them and we can increase and improve their outcomes — that does not seem to be the case for reasons that aren’t necessarily clear. But these high-risk patients with del(17p), complex karyotype genotypes, are not the ones who seem to be benefiting from the addition of that anti-CD20.

When you look at the rest of the comers, basically almost everybody else seems to benefit in some way, shape, or form. Those patients with low-risk mutated IGHV, when you take them as a whole patient group, they seem to benefit. But when you look at the subgroups, there’s kind of just trends towards it, and these patients have very, rather indolent disease. They’re going to do well probably with or without anti-CD20. This is a continuous therapy treatment.

And so, I think, while initially they seem to be very sensitive to anti-CD20 with continuous therapy treatment, these lower grade type of intermediate- to low-risk CLL seem to benefit just as well with monotherapy. And you can maybe get away from all of the baggage that you get with anti-CD20.

What starts to be clear here, though, is that the unmutated IGHV patients are starting to maybe derive some of this benefit, where you see many more of these subgroups are favoring the anti-CD20 addition, particularly higher-risk disease, not as bulky disease. Anti-CD20s aren’t necessarily that good at getting to disease bulk, so that’s not surprising necessarily to me. And even older patients.

So it’s hard to know what this is. We do know that response rates are higher. We see about 30% complete remission rates very early on with the addition of the anti-CD20. We actually see peripheral blood MRD much improved in this 30- to 40% range when you add in the anti-CD20.

So, is this an effect of deeper remissions? And if a patient were to have a toxicity or something, they come off of treatment or dose reductions, they actually are already in a deeper remission and that might be reflective in the PFS. I’m not so sure. These are thoughts of my own and hypotheses, that it’s possible. We may need to explore that a little bit better. But these intermediate-, higher-risk clones, like unmutated CLL, seem to be benefiting. And maybe that is the group that, if we’re using acalabrutinib we start to think about this to maximize the depth of that response, that remission, and potentially have that translate into some longer-term outcome in terms of keeping them in remission.

So the next thing here, and this study, I’m having a hard time necessarily interpreting fully, but I’ll give you my input here. So, this is Ryan Jacobs. He did a real-world comparison using some of these larger databases, kind of like a flatiron database, but this is using one within a system that has a well-curated database. And this was looking at the time to first — time to next treatment in patients on first-line treatment with ibrutinib versus acalabrutinib. And kind of a surprising factor here is that you in fact so that patients on acalabrutinib were more likely to initiate a next trial — next treatment during the study period.

Now, this is a little veiled though. When you look at the methods, et cetera, they essentially censored people if you went from 1 BTK inhibitor to another BTK inhibitor and did not necessarily count that as a next line of therapy. And that was to exclude any intolerance, et cetera. And what I think we’re seeing here is that if patients are on a second-generation BTK inhibitor, if there is an intolerance, much less likely to go to ibrutinib rather than the vice-versa.

And so, I think if they have an intolerance and all of a sudden how this database worked is that they then looked at another prescription being sent, and if that prescription was venetoclax, they got counted as a new treatment. And I suspect that some of these patients may have had an intolerance and actually, instead of going to a different BTK and being censored, they were actually flipped to venetoclax and then counted actually as a time to next treatment, which is right. And it’s the appropriate way to look at it but is it necessarily due to absolute progression and failure of the disease, I’m not so sure. Because that’s what this might suggest to you, is that, oh, acalabrutinib patients are needing treatment sooner, et cetera.

So, I think this study is nice. It kind of leads into also this other effect that maybe there are toxicities with acalabrutinib that we do see, and I think we underestimate some of these second-generation BTK inhibitors in terms of their toxicity profile.

So that’s a study here, that I wanted to kind of put out there and just state my own difficulties trying to interpret this data. But my thoughts on it.

DR LOVE: Are there any indirect comparisons that suggest any efficacy difference between the two?

DR ALLAN: We don’t have any indirect comparisons. Some of these studies are being done and there have been some kind Bayesian statistical analyses that have been reported and are ongoing to be reported to try to understand these differences. Obviously, we have the ELEVATE-RR study, which was acalabrutinib versus ibrutinib. And that was not inferior. It hasn’t shown any efficacy differences in terms of inferiority and/or superiority. But I think these are equivalent drugs. And I would like to talk with Ryan about this, honestly, to maybe pick his brain about what his thoughts were. Because in the abstract, it necessarily as in-depth, the meaning of what this means.

DR LOVE: If I could bring up one other issue, and when we get into the issue of efficacy, I was looking at your CV and I saw a paper you did, 2021, it was actually somehow a Letter to the Editor: Comparative Analysis of Target Novel Therapies in Relapsed/Refractory CLL. And if I understand this correctly, in terms of how you looked at it, it suggests you saw greater efficacy with venetoclax than BTK. Did I read that correctly?

DR ALLAN: Yeah. I mean these real-world analyses; I think we have to take somewhat with a grain of salt. They’re not necessarily as cleanly, well-curated in terms of true response rates, et cetera. But in general, yeah, I mean venetoclax, we have seen it’s a great drug to salvage BTK failures. I think this is much better than what we’ve seen in terms of going to a PI3-kinase inhibitor or something along those lines.

And I think the next question to ask, now that we are starting to see reversible BTK inhibitors become available, is it going to be the right thing? If you are progressing on a BTK inhibitor, to stay on a drug like pirtobrutinib, and stay within this “BTK inhibitor” class, and we’ll see some of this pirtobrutinib data later, versus, hey, you’re progressing on a BTK inhibitor, let’s switch completely to venetoclax where we know we’ve got really good data. You can get MRD-negative states. You can actually get complete remissions rather rapidly and really control proliferative, high-risk disease.

And I think that’s the next question of how perfectly to sequence, now that we’ve got drugs that actually, like reversible BTK inhibitors, pirtobrutinib, that can overcome true BTK resistance.

DR LOVE: But just looking, I know your paper there was in relapsed disease. But just looking across the papers available — the data available right now in the first-line setting, sort of the global message that I’ve been hearing for a while has been in terms of efficacy, at least in terms of BTK in general versus venetoclax, that people sort of viewed them equivalent. Any reason to think one is better — I mean I think you do see better, deeper remissions with venetoclax, but I don’t know if that has translated into efficacy. Is there any data to suggest one is better than the other?

DR ALLAN: No data. We have no head-to-head data prospectively. These studies are being done, CLL17 is going to be kind of a landmark study, the German CLL Study Group, that’s fully accrued. It’ll be a few years before we see some topline data coming out. But that’s looking at ibrutinib monotherapy versus ven/G versus ibrutinib/venetoclax.

I think what we will see is that any fixed duration approach that we use will probably have a modestly, if not statistically significant inferior progression-free survival to any continuous therapy BTK inhibitor approach that we use.

The issue is, is that while that PFS may be inferior, and people may need treatment slightly sooner, they’re still going to be off of drug many, many years, with deep, deep remissions. And I think we’re still going to struggle with is, like, okay, if a PFS for Ven/G is met at 6 years and we know with ibrutinib it’s somewhere around 8 years, does that mean Ven/G is not a good approach for the vast majority of patients? There are so many pros to being off of drug — financial, just other toxicities, physical toxicities, et cetera of the drug — that six years median PFS is still a phenomenal treatment and you’re off of therapy.

And then the other question is, what does that retreatment data look like? And we’re starting to gain that a little bit, but we don’t have a lot of good data because still, in CLL-14, for specifically speaking, a third of patients on the ven/G arm actually are getting some chemotherapy or BTK inhibitors. They’re not actually being retreated with venetoclax. Sixty percent of patients get a BTK inhibitor at relapse. A third of them got chemotherapy. And only about 15- or so percent actually were treated with venetoclax/obinutuzumab.

These numbers will probably shift as longer remissions occur and people emerge from longer relapses. Because I think when we see early relapses we don’t want to retreat, and, therefore, you’re going to switch to a BTK inhibitor, et cetera.

DR LOVE: I mean I’ve got to say I wasn’t even aware that the PFS was different. We did a webinar last night on prostate cancer, so I don’t know whether that’s sort of in my head, but we were talking last night about intermittent therapy, where they give ADT, and then they hold it to let them feel better, and then they restart it. I mean you could look at it venetoclax and the venetoclax on relapse if you view that and really it’s kind of the same treatment. And probably there, you would make up a lot of ground.

DR ALLAN: Yeah, absolutely. Matt Davids actually has a study that has launched, and I think they’ve accrued a few patients, it’s called the REVENGE study and it’s a great study. It’s a small, Phase II, but they are systemically asking this question where they’re taking patients who were treated with classic venetoclax/obinutuzumab previously, who then relapse. But there is no other option, they go on and get another 1 year of venetoclax/obinutuzumab. And I think that’s going to be a very important data set. The issue is, is I’ve been using this combination for quite some time on clinical trials and my first patient that I treated in 2016 has just now relapsed. And this didn’t really become widespread until 2020. So we still don’t even have a lot of these patients because the vast majority of young, fit, get to MRD-negative states and remain in remission. And somewhere around this 5, 6 years median, probably.

DR LOVE: Not to mention that the patient you start on treatment now, 6 years from now, who know what’s going to be going on. Compared to 6 years ago, so…

DR ALLAN: Exactly. So it’s an exciting time.

DR LOVE: Probably will be something else going on by then. By then it’ll be like probably pirtobrutinib and something else, some bispecific or something. Who knows.

DR ALLAN: Absolutely. Absolutely. And so, I think it’s an exciting time, but sometimes these questions are tough to answer just because the treatments themselves currently are just so good right now.

Updated data from the GLOW study: First-line fixed-duration ibrutinib and venetoclax compared to chlorambucil and obinutuzumab

DR ALLAN: So now we can flip to the front-line studies, kind of where the future is moving towards. And I honestly thought we were going to absolutely be there and that this was going to answer a lot of the questions. But I have actually swung back a little bit to say, hey, maybe triplets and doublets aren’t for everybody and maybe we don’t need them actually for everybody. But I do think they do benefit some certain subsets of patients. And I do use them, and I do think about them for certain types of patients. And they do have some good data behind them.

So there was a whole session, and now, at future ASHs, I think we’re going to see this very commonly, there’s going to be just whole sessions on combination approaches. And that’s what it’s been like for the past couple of ASHs. And so, there was a whole front-line combination session and this was looking at Carsten Niemann’s GLOW updates, which was nice and important. We’re going to see some important data from there.

I was fortunate enough to present on behalf of the authors, the update from CAPTIVATE, showing these patients who were in deep MRD-negative remissions, how are they doing on placebo versus continuation? And again, establishing the relevance of fixed duration.

Tom Munir presented the FLAIR study. This is a limited analysis, but there were some helpful things there. This is really looking at just MRD data, no real long-term PFS or overall survival data necessarily. But this was looking at I+V versus ibrutinib-based approaches.

And then Katherine Ryan from Matt Davids group and Dana-Farber, presented his updated multicenter, Phase II study from AVO. So, some triplet regimens, and we’ll talk about some opinions that I have there.

And then Eugan Tausch from the German CLL Study Group did some nice analyses, looking at genetic subgroups and markers that might predict inferior outcomes once you have a fixed duration approach, et cetera. So we’ll review that. So we’re narrowing in who it is that may fail and what approaches might be better.

So here is the now updated data, so about 3.5 years now median follow-up or so. GLOW, as a reminder, was ibrutinib plus venetoclax, 3 months of ibrutinib lead-in. Twelve months of ibrutinib plus venetoclax. And all patients stopped treatment regardless of their response. This was a randomized, Phase III clinical trial against chlorambucil/obinutuzumab, which has achieved approval in Europe and in other places in the world, based on this clinical trial.

And early on we see that fixed duration ibrutinib plus venetoclax now at this 3.5 year mark, PFS is about 75%. We know at about 5 years with ibrutinib monotherapy continuous treatment, we see a PFS of about 70% at 5 years. So, yeah, it’s there. It’s tracking historically well. Ideally, and excellently here, is that patients are off of therapy.

So historically, looking good. I think has established this approach as a very viable fixed duration approach. The synergies are there. And these patients who get into remissions and particularly MRD-negative remission, can do very, very well.

One thing that is exciting to see and nice to see here is that, early on, the overall survival, there was no overall survival benefit. And you actually saw maybe, kind of this signal for early deaths in this ibrutinib arm. And that wasn’t necessarily just due to infections and things. There was cardiac deaths. The issues that plague ibrutinib studies has been seen in this study. Mind you, this is in older patients, et cetera. The median age was 70 or so.

So now with this further follow-up, we are seeing this overall survival benefit favoring ibrutinib/venetoclax. And that really is coming from, I think, the important part of the immune system where once you stop treatment, and you don’t get long-term anti-CD20 and chemotherapy, that immune system recovers. We actually have some pretty good data there. And what we’re seeing is that there are a lot of late deaths due to infections in the chlorambucil/obinutuzumab arm that were not seen in the ibrutinib/venetoclax. And so, I think these now have stabilized and crossed and now we’re seeing this rather pretty strong signal for overall survival benefiting the ibrutinib/venetoclax combination arm.

DR LOVE: So I know you’re going to go over other studies but just looking at this one. If you were to take the progression-free and overall survival curves from BTK alone and venetoclax/obinutuzumab, how would it be compared to the lines — I mean, of course, all the caveats of indirect — but just grossly, it kind of looks to me like it’d kind of be around the same place. But you tell me.

DR ALLAN: Yeah. No, I agree. So the nice thing about these studies is that they are all pretty done in the same type of patient population, all greater than 65 years of age, or with comorbidities, et cetera. And always have a nice, good balance of patients.

Now these ibrutinib studies, CLL14 did allow del(17p) patients into it, whereas GLOW did not. And so that has a little bit of effect, but for the most part, those are minorities of patients that are enrolling in these studies.

But to your point, we know in CLL14, at 5 years the median PFS for the entire population is 64%. Here we are at 3.5 years in the GLOW study and it’s 75%. So tracking historically well, along with what we’ve seen in ven/G in these older patient populations. And mind you, this is an anti-CD20-free regimen. And this was done in the era of COVID and all these kinds of things. And so, there are some benefits to it. And I do think anti-CD20 does have some prolonged immunosuppression that can create some havoc sometimes in some of these later infections that occur.

So historically well. We see in continuation BTK inhibitors, maybe the PFS is a little bit better. I think any fixed duration approach study, we are starting to see particularly higher-risk patients start to separate themselves. And if anything, that was a big theme from this session at ASH. And so I think we are seeing this. But, again, the outcomes are still so good and you’re off of therapy, and there’s a lot of these benefits that, as of right now, we’ve never shown an overall survival detriment to stopping therapy early. And so, therefore, these regimens are all in play and I think are very viable for most, if not all patients. And basically, we need these head-to-head studies, still, to really help us decide the relevance, the absolute relevance of our sequencing and our approaches. And maybe we swing all the way back to say, hey, it’s best to just sequence these drugs one at a time, rather than putting them all together because you may not need to do that.

DR LOVE: And again, I don’t know to what to extent patient reported outcomes have been done for all these studies, but just, rather than thinking about data, just thinking about your own clinical experience in terms of quality of life and other issues. You would expect that quality of life would be better than continuous BTK and certainly the expense is going to be less, I would think with just straight BTK. But what about comparing it to just obinutuzumab/venetoclax in terms of the patient experience? How would you compare it? They would have to come in for the obinutuzumab. You bring up the potential of more infections. How would you compare quality of life, let’s say obinutuzumab/venetoclax versus venetoclax plus BTK?

DR ALLAN: So some of these analyses are starting to be done. And I can’t quote them all off the top of my head. But now that we’re getting longer follow-up, we are starting to done 1, these quality-of-life questionnaire assays — tests and getting that data. We’re also doing these economic impact analyses as well to help guide payors and what is the best approach, et cetera, there. So that kind of research is being done and is generating more and more with every year.

You bring up some good points. There are patients that are on ven/G that I’ve stopped; they’ve gotten to their year and they did great with it. But then all of a sudden they get off of drug and they’re like, oh, yeah, this queasiness or whatever, this GI upset that I thought was not a big deal is, all of a sudden it’s gone and I don’t have this. So there is benefit towards this. I think getting off BTK inhibitors is ideal, although, with that said, patients self-select. Once you get beyond 2 to 3 years, and you haven’t had any toxicity, you typically don’t have any issues with the drug.

So, we do see some immune benefits getting off of these agents. The CAPTIVATE study has shown some of that data where the B-cells come back; the T-cell activation comes back. And we do see changes in populations once you stop these drugs. And so, I think there’s absolute benefit to kind of some immune reconstitution as well. And that’s to the benefit more for these oral therapies that exclude the anti-CD20 because that is very long-lasting B-cell depletion.

With that said, we also have now 8+ years of experience of continuous therapy BTK inhibitors. And patients are doing still well and we’re not seeing major, major issues, particularly those who are long-term.

So I don’t know the right answer. I don’t know the absolute best approach. But I do think getting off of drug does have an effect on some of these longer-term toxicities. And patients do seemingly feel better when they get off of these agents, if they are able to.

So the next big, I guess graph that was shown from this study, and what I thought was really important was that the disease kinetics and kind of the outcomes based on how you were doing, based on some of these features.

So, again, we are starting to see those patients with CLL who have IGHV unmutated disease, once you stop treatment, you will have an inferior progression-free survival. This has been seen in CLL14. This is now seen in GLOW. This has been seen in various other fixed duration approaches. Once you stop treatment, these higher -risk, intermediate-risk kind of CLLs will start to grow back faster. And they have an inferior progression-free survival. This is no different with ibrutinib/venetoclax.

As you can see here on the left, the progression-free survival for the lower-risk mutated IGHV patients looks phenomenal. They’re doing very well, 90% at 3.5 years. That’s kind of unprecedented type of PFS, whereas those with unmutated IGHV, somewhere in this 70% range at this 3.5-year mark.

One thing that was, I think, kind of unique is that when you looked at patients, what we are starting to learn is that patients with mutated IGHV CLLs, when they get all oral BTK/venetoclax based approach, they actually get to an MRD-negative state less likely than those patients with high-risk disease. This is something that’s now been seen in pretty much every single oral, all oral combination study.

And reasons behind that aren’t necessary clear. We do know that unmutated IGHV typically is more sensitive to initiation of BTK. There seems to be much more activation of the B-cell receptor and this leads to potential increased synergies between that and venetoclax.

So, when you look at IGHV mutational status, the unmutated patients with I+V out of the CAPTIVATE study, close to 85- to 90% of them were MRD-negative in the peripheral blood. And it drops down to, in this 50% range for the mutated IGHV patients. And so, when you look at all-comers, the best MRD-negative state for all-comers in all of these studies is in this 65- to 70% range as best overall. And I thought, fixed duration that was going to be it for everybody. Everybody was going to get to an MRD-negative state at 70-, 80% of the time because of these synergies. But that’s just. Not the case.

What is important though, and what this study has shown, is that you can see that the low-risk IGHV-mutated patients, even if they don’t get to an MRD-negative state, once they stop treatment they actually do really, really well still. And so, maybe we don’t need to get everybody there. Most of these patients are in this low MRD-negative state, less than 1% of CLL still circulating in the blood. Those patients who do get there, do phenomenally well. And what you can see here is that the IGHV-unmutated patients, clearly these are the ones that we want to maximize, that we want to get to an undetectable MRD state. Fortunately, 80% of them typically do. Very few of these patients are in this positive state. But maybe, these are the people that we don’t worry — or that we think about, hey, maybe we should continue on treatment, maybe we should leave them on a continuous therapy BTK inhibitor, and maybe we shouldn’t necessarily stop them. Because they are going to progress sooner, particularly if they’re MRD-positive.

But that is what the big take-home here for me was that these lower-risk patients, even if they’re MRD-positive, I don’t think we need to worry so much about them, and it still provides a fixed duration approach for the if we use I+V for these lower-risk patients. Because they’re still going to do phenomenally well once you stop treatment.

Treatment outcomes after achieving undetectable minimal residual disease (MRD) with first-line ibrutinib and venetoclax: Updated analysis of the CAPTIVATE trial

DR ALLAN: The next study here was the CAPTIVATE update, and this is what I had participated in and presented. And so this study, this update was unique in that it looked at just the patients who had confirmed MRD-negativity. So, this study required same treatment, 3 months of ibrutinib, then 12 months of ibrutinib plus venetoclax. After that 12 months, patients were randomized to either continuation of placebo or ibrutinib, if you were MRD-negative. And if you were MRD-positive, you were randomized to continuation of ibrutinib versus ibrutinib plus venetoclax for another year.

What this update looks at, focuses on, is those confirmed MRD-negative patients, how do they do after they were randomized to placebo or ibrutinib? And this focuses on those 86 patients. There’s 43 randomized into each arm.

Now, because they used this confirmed MRD-negative definition, the amount of patients randomized was about 55% or so even though the best MRD in this study was in the 70% range. Because the confirmed definition required serial MRD-negative states in the peripheral blood and the bone marrow.

And so, a little over half of the patients were randomized to ibrutinib/placebo. What we see here is that in terms of the disease-free survival, it was about 83% versus 95% in the ibrutinib arm. So those patients who stopped treatment, they do have MRD-relapses. They don’t necessarily have true progression. But at this 4-year mark, 3 years off of therapy about, they looked very favorable.

When you look at true progression-free survival on the left here, you can see that, yes, maybe numerically the placebo arm is starting to maybe start to progress a little bit sooner than those who remain on ibrutinib. But, in general, this is a very favorable outcome still, and looks like a very positive result in terms of confirming that if you are MRD-negative, you can probably safely stop ibrutinib or any continuation therapy and remain in remission for quite some time.

And then, again, the same story being told here, is that the unmutated IGHV, will start to separate themselves a little bit here. so those who had true fixed duration they didn’t remain on continuation.

The unmutated IGHV again is starting to separate itself as time goes on. These clones are going to grow back sooner. Those mutated patients are doing, still, very, very well, regardless of if they’re on placebo or ibrutinib. But you can see that maybe ibrutinib in continuation of treatment can really lock in this MRD-negative state and they’re going to do really, really well. The issue is, is that you’re now talking about a continuation therapy and the whole value of these fixed durations is being able to stop. But in these super high-risk patients, I do think that we’re starting to see unprecedented progression-free survivals in these combination patients that have really high-risk disease.

And that’s where this slide comes into play. So one is just on the left, you can see that the patients who attain an MRD-negative state with ibrutinib plus venetoclax maintain it basically. So they’re not rapidly progressing. These remissions remain very, very deep, although CAPTIVATE didn’t look at depth of remission in terms of using ClonoSEQ and getting down to 1 to a million. We know from other studies that I+V can induce very, very deep remissions, where over half the patients are 1 to the 10^-6 or deeper.

And so, when you can achieve that, that MRD state is going to be very durable over time. And that’s kind of what we’re seeing as we’re now getting more and more cycles post-randomization.

And then the other just high value yield thing here is that when you have high-risk patients, so we separated out the 26 patients with del(17p), p53 or complex karyotype, when you separate those patients out, placebo or ibrutinib, you see no real difference. I think we have to study this a little bit better because it was unbalanced. There was no stratification at time of randomization based on high-risk features, necessarily. And so, there were more high-risk patients getting maintenance ibrutinib. But one thing I’d like to bring out is that yes, fixed duration approaches looks good for them, but when you look at 95% PFS in these 20 patients who got an MRD-negative remission who remained on ibrutinib, I mean these unprecedented 4-year PFS’ for these types of patients after any type of treatment.

And so, we’re really starting to move the needle, particularly in high-risk disease, where I think ideally I+V or BTK inhibitor venetoclax combinations have the best role, particularly in these complex karyotype, (17p)-deleted patients.

DR LOVE: So I never thought to ask anyone this, but this just popped into my head. In these trials, or these combination trials, in general, what do they if the patient developed a BTK toxicity, for example, atrial fibrillation? And was it different if they got it during the induction BTK part, or during the combination? Or when during the combination? Did they get thrown out of the protocol? What happened?

DR ALLAN: So, great questions. So, fortunately with CAPTIVATE, these were all young patients. And so the tolerance of this regimen was much greater than in GLOW. And so, in this study, 95% of patients actually completed all 12 cycles of the combination treatment or were eligible for randomization. There were very few patients that fell off. I think out of the 164 that enrolled in this MRD cohort, I think only about 7 failed to randomize due to coming off of the drug. But essentially, if they had discontinued 1 or the other, ibrutinib or venetoclax, or even both, they were ineligible to randomize.

Now, fortunately, because it was in younger patients and they were just allowed to continue on treatment and, essentially, came off of study after the 12 cycles, basically.

But because this was young patients, the vast majority of patients were, in fact, able to randomized. It is also very tolerable. That is in comparison to GLOW, where only about 75% of patients, in this older patient population group, were actually able to complete all 12 cycles of ibrutinib plus venetoclax. There was definitely more dose reductions, dose discontinuations and dose interruptions in that older group. And so, again, I+V, while it’s tolerable, does have increased diarrhea, does have some neutropenia and cytopenia issues. We do see these cardiac issues. But clearly, it’s much more tolerated in the younger patient population where, I think — while GLOW, its registrational status was in older patient population, ideally this is still maybe for that fit, 70, 75-year or younger type of patient. And I don’t think we need to be giving our 80-, 85-, 90-year-old patients combination treatments, honestly.

DR LOVE: And that’s another thing I never exactly understand, why do you do you trials that are just older people? Seems like once you do it, then you give it to the younger anyhow. But why are the trials designed that way?

DR ALLAN: I think in CLL, in most cancers and malignancies, I think that is where the vast majority of patients are. I think that is where chlorambucil/obinutuzumab, which a lot of these are randomizing to, had some role. So I think there’s a lot of factors outside of just for study design factors and feasibility, what can you actually get away with. And it would be hard to entice a young, fit patient to chlorambucil/obinutuzumab. So you kind of have to go into this older patient, unfit population to be able to do that. That’s not a great answer. But outside of just the population of where CLL is, which is majority median age of 70 at diagnosis. With that said, when you look at these trials, most patients are kind of in their 60s, and it is a slightly younger group that is enrolling in these studies. And that’s for a lot of other reasons as well.

DR LOVE: Another question I just had coming in here, and maybe this is a good time to bring it up. You were talking about analyses, looking at data like Flatiron, et cetera. And recently, I heard about some data suggesting to my surprise, that there’s a fair amount of first-line chemoimmunotherapy being used in the United States. And the question is, is that true? And second of all, if so, what’s the reason?

So, (A) do you think that’s true?

DR ALLAN: Yeah. I mean, when I talk to colleagues and talk with colleagues out in the community who aren’t necessarily just CLL non-stop and lymphoma non-stop, majority at this time seem to have all converted over to using novel targeted agents. When you look at market data from pharmaceutical industry and things like that and trying to understand, we see this base of 30% of patients still getting chemoimmunotherapy with CLL.

And so there is a disconnect from what I hear when I talk to people, from what the actual claim’s data show. And that I don’t quite know why. I think the recognition that these drugs are there and available are out there, I think there is a lot of conversion occurring. I do think we’ll start to see this continually diminish and go away. But I don’t have a great answer of why it persists.

DR LOVE: Well, I have a hypothesis and I want to know what you think about it because I actually would like to study it. Because I hear people going, oh, it’s because oncologists don’t know that you don’t use chemoimmunotherapy anymore. But I mean, it’s like in the NCCN Guidelines, UpToDate, I mean it’s all over the place. I don’t believe it. I’ve never even talked to — I mean, yeah, maybe I talk to people who are more up-to-date. But I’ve never talked — I think it’s because — because all they’re looking at is what they ended up on treatment. I’m assuming it’s issues with being able to get the drug financially.

DR ALLAN: Yeah. I think there’s a lot of, not misinformation, but misunderstanding out there about co-pay assistance programs and how available are these drugs. And I think you hear a patient say, oh, I don’t want to pay anything. And if there’s any risk of me having to pay something I don’t want that. And if you don’t quite know and/or have a pharmacy and a team that can help you fight these prior approvals and these authorizations, you may really reach for what’s easy, tried and true, and that’s chemotherapy. But once you prescribe these drugs, I really know financial toxicities for the majority of patients, Medicare patients, and/or private-insured patients.

So I’ve never really come across is financial issues being a reason that I couldn’t get the drug. So I think that is potentially viable, but I think it’s due to more of a misunderstanding of the true scenario rather than reality of it.

DR LOVE: Well, this was brought up to me as potentially a CME issue that, like I said, people don’t know the data. But maybe it is a CME issue that they don’t know how to get the drug through these other programs because they don’t have the experience that you all do. I don’t know.

DR ALLAN: Yeah. And I think there is a lot of unknown things about what is an actual cost and what is the wholesale acquisition costs? And we don’t know these things. And what is the potential out-of-pocket costs? And I’ve had reps come and I’ve sought that information out because I do counsel patients on it frequently. But if you don’t have that time and you’re using a million different TKIs and you’re treating breast cancer and colon cancer and not so much CLL, it’s not necessarily different with any of these other oral targeted agents. But I don’t know. I don’t know the hesitance. And I don’t know if I have a great answer of why we still see kind of chemoimmunotherapy as a base here.

DR LOVE: Well, if I can figure out a way to get it studied maybe you can help me?

DR ALLAN: Yeah, absolutely. I think it’s a very important question to understand.

DR LOVE: I mean if it’s really 30%, that is a huge number.

DR ALLAN: Yeah, that’s what consistently comes back when I see this data presented. It’s just eye-opening and you try to understand. Because there is an absolute disconnect from what you hear from colleagues. And maybe it’s regions of the US where I’m speaking to and talking with. But I just don’t know.

DR LOVE: All right, please continue.

Ibrutinib/venetoclax with MRD-driven duration of treatment: Updated analysis of the FLAIR trial

DR ALLAN: So, the last study here, and I don’t want to spend too much time ono this abstract here. This is the FLAIR study. And FLAIR is being done by the UK Group. And it’s a great study. Again, it’s a 4-arm study looking at FCR versus ibrutinib. That’s how it originally started. And then they started to add arms: ibrutinib/rituximab, ibrutinib/obinutuzumab, et cetera, and they added an I+V arm.

So this cohort was added late. And this cohort was added statistically and powered to look at MRD against ibrutinib. Which, I don’t know, that’s not going to give us any answer that we don’t know is going to occur. We know ibrutinib plus venetoclax, going to get more MRD-negative states than ibrutinib. But that’s how it was powered and that’s what this primary analysis was presented at.

And so, I don’t want to belabor that because we see about 70+% of patients in general, get to an MRD-negative state in the peripheral blood with I+V and almost no patients get there with ibrutinib in the 2-year mark.

Now, this study was also unique in that it determined how long you would get treatment based on how fast you got to an MRD. And there’s some complicated mathematics, et cetera. But outside of that, at 2 years, we see that 80% — and again this story being told, the unmutated IGHV patient, 80% of them are MRD-negative in the peripheral blood compared to 56.4% of those IGHV mutated.

And then on the right here, the time to undetectable MRD, the red is the unmutated patients. So they get there faster. They have very sensitive disease. And then this continues to deepen over time of the percentage of patients that get there. The mutated patients lag in the blue arm here, but you can see that again, bringing into question here, is a fixed duration approach right for everybody? Should it be a response-adapted approach? And if you’re MRD-positive, maybe continuation of some therapy might be able to convert you with additional exposure and treatment.

So we start to see these patients get there. This is the peripheral blood on the top and the bone marrow on the bottom. And you can start to see, it continues to increase over time; doesn’t necessarily plateau though. Maybe we’re starting to see that with the IGHV-mutated arm here.

Regardless, we see this disease sensitivity. This was kind of the big highlight there, not anything that we didn’t know, but it kind of solidifies the biological differences between these 2 CLLs and their sensitivity to ibrutinib plus venetoclax.

Acalabrutinib with venetoclax and obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL) in a population enriched for high-risk disease

DR ALLAN: Then we get into the triplet regimen here. Katherine Ryan, who is working with Matt Davids at Dana-Farber, presented their updated Phase II study where they added a cohort of patients with just high-risk del(17p) disease. And these patients, the primary endpoint was MRD-negative states in patients who achieved a complete remission only.

When you look at it though, what we see is that anti-CD20 does seem to probably add something to the MRD-negative state. You can see here, all patients, we’re looking at 86% of patients getting MRD-negative in the peripheral blood at cycle 16 and in the bone marrow. Whereas, when we look at I+V without the anti-CD20, we’re seeing this probably in the 70- to 60% range in the peripheral blood and the bone marrow. So I do think it adds something to the treatment. It definitely does add toxicity as well — infections, neutropenia, cytopenias. And also, the fact that you have to get the regimen and the induction and this kind of stuff. So logistically, it becomes more complicated.

I think we are going to start to see clinical trials, and I have a study coming out soon, looking at late edition of the anti-CD20 after oral combination therapy in patients who are MRD-positive only.

So I think we can maybe get to the same place here of 86+% of patients getting to an MRD-negative state without exposing every single patient to anti-CD20 therapy and really just focusing on those who might need it.

Additionally, this was done in high-risk disease patients. And we just saw acalabrutinib plus obinutuzumab didn’t really seem to benefit from anti-CD20 but does that matter when you throw in venetoclax into the mix. It remains to be seen.

Regardless, high rates of MRD-negative with AVO. These patients were able to stop treatment if they met these prespecified, strict criteria of confirming an MRD-negative state. Follow-up is relatively short, but the PFS and overall survival looked great. I think out of the 60+ patients enrolled, I think maybe only 4 have had any disease relapse — MRD relapse and/or progression. So they’re doing phenomenally well. Many patients, this treatment extended out beyond cycle 25, too, for these patients who remain persistently positive.

So they’re still on treatment. Great regimen. Very safe regimen. And, also, is providing great evidence of and setting new benchmarks for what to expect going forward.

Risk factors to predict failure of therapy using fixed-duration venetoclax/obinutuzumab 

DR ALLAN: And the last thing here is just some data identifying what are risk factors to predict a failure from venetoclax/obinutuzumab fixed based approaches. And this was a pooled analysis and I just focused on what is unique for ven-based approaches, not what’s compared to chemotherapy because that’s kind of irrelevant in this day and age. But from the CLL13 study, which is a big, huge study looking at ven/rituximab versus ven/G versus the triplet, ibrutinib/venetoclax/obinutuzumab, against chemoimmunotherapy, both co-primary endpoints had been reported at previous Congress’ showing really high rates of MRD-negative states for the venetoclax-based approaches over chemoimmunotherapy — I should say venetoclax/obinutuzumab-based approaches.

This study, I think, has confirmed final and foremost that rituximab is an inferior antibody in CLL. The obinutuzumab-based arms statistically have improved MRD-negative states compared to the rituximab-based arms.

We’re seeing in venetoclax/obinutuzumab in the triplet regimen, MRD-negative states in the peripheral blood after the 1-year of therapy, upwards of close to 85- to 90%. So really, really active regimen in these young patients. And so, it looks really, really good. And what we’re seeing here though is who is going to progress sooner? And that’s kind of the point of what this abstract looked at. Eugan Tausch presented this data.

And what we’re finding is again, the story that’s being told, unmutated IGHV, these patients will progress sooner. They will have an inferior progression-free survival once you stop their therapy. And patients with complex karyotype, not surprising, high-risk disease, highly proliferative clone. Patients with elevated beta2 microglobulin, again kind of correlates into high-risk disease. This is part of the CLL IPI. This is part of the CLL4 scoring systems. If it was elevated or markedly elevated, it’s a point against you and a risk factor for more aggressive disease.

And then what was unique about this, in all of these studies that have been done, continuous therapy, BTK inhibitors, we’ve never really found a mutation that has identified an inferior PFS. Here, we see RAS/RAF mutations and NOTCH1 mutations independently predicting inferior progression-free survival with venetoclax-based approaches.

And so, again, genetic subgroups that we’re starting to learn that maybe we need to worry about a little bit more, that if you find those patients in your group you watch them closely. You think about them maybe a little bit differently. And how to act on this, we don’t quite know, but at least identifying the patients we need to worry about is the first step to being able to intervene.

Updates on the ALPINE and BRUIN studies of zanubrutinib and pirtobrutinib, respectively, for relapsed/refractory CLL

DR ALLAN: So, with that, I can just go back to relapsed CLL now.

This is true quality of life survey results from the ELEVATE-RR study.

It just shows you that second-generation drugs, BTK inhibitors, are better tolerated and translate into improved quality of life and AE burden scores, et cetera.

Here we are seeing the AE burden score being decreased with acalabrutinib. And I don’t think this is surprising. I think, when we start to see the ALPINE data, we’re going to see very similar data here as well. And it just speaks to the fact that these are better tolerated agents.

So this is, the big splash here, this is Jen Brown presented this data as a Late-breaking abstract. This is the ALPINE study. It was published in the New England Journal as she went to the podium. So please reference the paper as well. But this is the study looking at ibrutinib versus zanubrutinib in all-comers relapsed disease, kind of the counterpart study to the ELEVATE-RR study, which was acalabrutinib versus ibrutinib. And what’s unique here is that this one, zanubrutinib was shown to have an improved superior overall response rate. But also what raised everyone’s eyebrows, about a year and a half ago, was that there was an interim analysis done showing a potential improved progression-free survival.

Now this has now been confirmed at this 2-year follow-up. There’s 30 months of median follow-up but the 2-year mark, landmark timepoint PFS has been confirmed to be superior for zanubrutinib versus ibrutinib, with 80% versus 67% in the ibrutinib arm.

This seems to improve in the high-risk patients and del(17p), where we’re seeing a 77.6% PFS at 2 years with zanubrutinib compared to 55% with ibrutinib. And so, I think this study confirms this PFS benefit over ibrutinib. I think we can pick apart this study comparatively to ELEVATE-RR — very different patient populations, very different numbers of prior lines of therapy — to tease al these little things out. But at the end of the day, this is a Phase III clinical trial and showing a superior PFS for zanubrutinib over ibrutinib in these patients with relapsed CLL.

The other big thing here is that we see the cardiovascular benefits of second-generation, more selected BTK inhibitors. Similarly, to acalabrutinib, this has a statistically significant benefit towards AFib. Here we see zanubrutinib have a AFib rate of 5.2% versus 13.3%. This is a median follow-up of 30 months, in ELEVATE-RR with a median follow-up of 40 months, we saw 9.6% versus about 16% AFib rate in the ibrutinib arm. So I think very comparable. Hard to say one is better than the other in terms of the safety profile.

The other thing that we see here is that we do not see these fatal cardiac events in the zanubrutinib arm. We saw 6 of them occur in the ibrutinib arm. So again, this story of ibrutinib with these fatal arrythmias and fatal cardiac events continues to occur. We still see this signal. And seemingly, we do not see this signal with acalabrutinib or zanubrutinib. And this is just more data showing that as well. Obviously, we need longer follow-up. We need to be monitoring for this. But it does seem somewhat specific for ibrutinib, though not to say that it can’t happen with these more second-generation BTK inhibitors.

DR LOVE: Any hypotheses if there actually is an efficacy advantage as to why? Dr Brown was trying to explain to me, like, pharmacologically how the drug was designed. Any thoughts about that? Do you see that as different enough that maybe you could explain this?

DR ALLAN: So with this drug development, they really pushed this dose pretty high to be able to penetrate lymph nodes, to be able to maintain a very elevated plasma concentration throughout the entire dosing interval. And what we see is, 1), it’s the only drug that we’ve ever been able to see BTK occupancy at 90% of greater in the lymph node at these various timepoints, with these various doses. But, 2), the PK data would suggest that the dosing – the dose level and the plasma remains well above the IC50 throughout the entire dosing interval.

So it’s constantly inhibiting BTK. It’s constantly inhibiting any newly synthesized BTK. And you might think that these more aggressive, more proliferative types of lymphomas might be turning this over, and if you’ve got drug around you can inhibit it and knock it out. Whereas with the other agents, it quickly drops below that IC50. And maybe that’s hypothesis-generating. We don’t really know that definitively. But these PK differences, I could see a reason why it works better, particularly in more aggressive disease, which we’re kind of maybe seeing a signal here in this del(17p) group.

DR LOVE: So, on the other side of the coin is, are there any things about the trial that may have led to these data, but not really reflecting an accurate difference? I remember when it first came out, there were issues about how they define progression-free survival and how they approach patients who have lymphocytosis. More recently, I’ve heard people talk about the number of patients, that they increased the number of patients in the trial.

Anything about the way the trial was done that could explain it, other than just the drug being more efficacious?

DR ALLAN: Yeah, they did move the needle a little bit in terms of adding more patients and increasing power, et cetera. I think there are a few things: one is that it is unblinded. So patients knew if they were on ibrutinib; patients knew if they were on zanubrutinib. Doctors knew if they were on ibrutinib or zanubrutinib. And two, the error of these studies were different compared to ELEVATE-RR. So this is lagging that by another year or so. And more and more data was coming out and safety data. So patients who know they’re on ibrutinib, maybe that’s going to play a role, and there’s going to be less tolerance to keep somebody on. And you come off of the drug for intolerance. And we do see safety data where zanubrutinib has less drug discontinuations, et cetera. But it’s very similar to what we see with acalabrutinib. In fact, 15% of patients still discontinued zanubrutinib compared to 22% of patients discontinuing ibrutinib for an adverse event.

So I don’t think that’s the whole story. I do think these drugs are better tolerated. But you can also argue that hey, they released an interim analysis that was early, that was unplanned, that showed a benefit. And how does that play into the patient? That physician? These biases are inherent. They are there for sure. Is it enough to really sway 15+% progression-free survival? I’m not so sure. The arms were pretty well balanced. And there is the other side of this, that the drug may, in fact, have this PK data behind it to suggest it might, in fact, just be a more effective drug. But there’s a lot of back and forth.

I don’t know if we’ll ever get an answer. We still have to focus that it was a well done study and Phase III randomized. And the data is showing this outcome.

DR LOVE: So here we go. If you see a patient today, they’re not going to go on a clinical trial. What are you likely going to do if you want to give them a BTK inhibitor alone?

DR ALLAN: So I have been using zanubrutinib, even before this data came out. Because of all these signals that we saw, and I kind of believed in this PK story, too. And so, well before this data came out, I was using it. And I also like the fact that you can use it as a once-a-day drug. There are patients who like once-a-day dosing and don’t want to be on a twice-a-day drug. So, I have used it as a once-a-day. It’s in the label, et cetera. And I typically start it out as twice-a-day, but once I get disease control and so on and so forth, if patients are having difficulty remembering the drugs, I flip it out.

Also, I started to early adopt it because the PPI issue — that’s really no longer an issue with acalabrutinib, but when I started to adopt it, that was out there. So I didn’t even want to think about that problem. But for all of those reasons, now with this data, it’s kind of solidified my use as a drug that I do like and I reach for frequently.

DR LOVE: Any thoughts about tolerability of acalabrutinib versus zanubrutinib? There’s no direct comparison. But looking at the data and also, your clinical experience.

DR ALLAN: I think the one thing that acalabrutinib may have and its advantage, is the hypertension signal. We see similar rates of hypertension with zanu — with ibrutinib, and I’ve seen that in my own clinic, patients get hypertension rather frequently. I’ve maybe seen it a little less with acalabrutinib. The data for acalabrutinib is 9% versus 23%, all-grades hypertension. Whereas, it’s 16% and 16% for the ALPINE data, which is the zanubrutinib data. And mind you, it’s less follow-up time, et cetera.

So, that is one signal that I think is unique to acala that is in its favor. So, somebody who’s got bad hypertension, I may not reach for ibrutinib or zanu. I think that’s somebody I would think about acalabrutinib for if they’ve got 3 drugs and they’re maxed out. And I may not even think of a BTK inhibitor for those patients, but if I am, it’s definitely going to play into my decision-making.

I think these other things like hemorrhage and diarrhea and arthralgias and skin rash and things like that I think are rather similar between the drugs. I can’t say that there’s less bleeding with acala necessarily, but I do see bruising and bleeding with zanu, and I think maybe there might be a slight advantage there. We saw slightly lower rates of hemorrhage, bruising and bleeding in the ELEVATE study, comparatively to zanubrutinib. But, again, this is where these kind of indirect comparison studies with common denominators, control arms, are going to be valuable to be able to potentially bring into the fold, kind of the best we’re going to get. Because we may never see these true head-to-head acala versus zanu study ever.

DR LOVE: I think I’ve seen some data on the tolerability of zanu in patients who are intolerant of acala. Not too much. I think I’ve seen a handful, maybe more. What about the other — is that true? And what about the other way? Do you see patients who don’t tolerate zanu and do tolerate acala?

DR ALLAN: Yeah. So, zanubrutinib has the 215 study. And that’s looked at 2 cohorts, so with ibrutinib and with acalabrutinib intolerance, that then switched to zanu. Acalabrutinib has ibrutinib-intolerance switch data, but not any data — because it was done in an earlier era before zanubrutinib was really even relevant — does not have really any data from zanu to acala. With that said, I think if you were having any intolerance with 1 of these agents, you can switch to another agent within the class and avoid that intolerance. And I think, now that we’ve got 3, I’m tempted to try all 3 before I really switch out of the class. But, as we’re starting with second-generation inhibitors and we’re trying to get away from potentially ibrutinib toxicities, maybe we’re just talking about switching between the 2 second generation ones and then leaving the class potentially, after that.

But there’s good dose reduction data with ibrutinib now. And I think we’re confident that even with dose-reduced amounts of ibrutinib, you can maintain efficacy and you can probably mitigate a lot of the toxicity — arthralgias and rash and even maybe cardiovascular events, et cetera — by even having early dose reductions. And that’s reflected in the prescriber insert.

So all 3 are good drugs. I think we can switch between all 3. I’ve got 1 patient that I’m about to switch to the third agent to see if this toxicity continues to show up. I have a small handful of patients that are in that type of scenario.

DR ALLAN: So, here is the pirtobrutinib data presented by Anthony Mato, and he’s been heavily involved in the BRUIN study here which put pirtobrutinib on the map. And, in fact, pirtobrutinib is now FDA-approved in mantle cell lymphoma after 2 prior lines of therapy.

So here, it’s not approved in CLL, but, in fact, has the most data in CLL. There’s like 300+ patients treated with pirtobrutinib on this BRUIN Phase I/II study.

And so now we’ve got pretty decent follow-up. As you can see here, we’ve set a median PFS for these patients who have had prior BTKi. And what you can see, even if you’re really heavily pretreated, 3 versus 5 prior lines of therapy, the median PFS looks really good at around a year and a half or so, approaching almost 2 years: 19 months for these 3 prior lines of therapy, 18 months for these 5 prior lines of therapy.

And so, this is a great option. Patients are going to be salvaged with this drug for a period of time. Obviously, it’s not an answer for everybody for really long periods of time — we’re not seeing years and years like we did with ibrutinib, et cetera, in these same types of patients. But this is a nice and welcomed treatment to our armamentarium and our arsenal. And, ultimately, the data looks really good, not just in terms of efficacy wise, but also safety. Which I didn’t put the safety in here.

But we see now in those patients, BTK, C481, again the median PFS is being met at around this 16-month mark. Age, p53 disrupted patients seem to maybe starting to separate themselves out. But, in general, all-comers, no matter what risk or what genetic features you might have, are doing phenomenally well, being salvaged with this drug. And we’re getting at least another year median extended in terms of outcome and efficacy.

This drug sems to be very, very safe. And has maybe the best toxicity profile of all of BTK inhibitors. Mind you, this follow-up is still only about a year and the others have years of follow-up. But right now we see very low rates of AEs, particularly AFib, in some of these nuisance things.

Emerging data with novel Bcl-2 inhibitors

DR ALLAN: I just wanted to flip to the BCL2 inhibitors. There were 2 new BCL2 inhibitors that were available with very early data; obviously, starting to differentiate themselves in terms of the ramp-up. Here, this one is called lisaftoclax being used in CLL. Matt Davids presented this data, with a daily ramp-up. So, venetoclax is currently being ramped-up over 5 weeks. Lisaftoclax, on this study, was ramped-up over 5 days before you got to your target dose. And this was either as monotherapy or in combination with acalabrutinib and/or rituximab.

What we see here is that you see response rates. This drug is active as a monotherapy, 67% response rate in relapsed/refractory CLL. There was a small cohort of treatment-naïve patients getting combined acalabrutinib data. But we see nice response rates and it’s occurring in BTK-resistant and -intolerant patients.

While we’re all hopeful for an easier ramp-up for BCL2 inhibitors, I do just caution that with the ramp-up of venetoclax, we basically don’t see any lysis, whether it’s laboratory or clinical. And in this small study, they did actually see 2 clinical tumor lysis syndrome. While the patients were fine, they did meet clinical tumor lysis syndrome. And so, this is something we’ve essentially mitigated and eradicated from a slower ramp-up. So I think it just gave me some pause to see this fast ramp-up and starting to see clinical tumor lysis syndrome occurring. And maybe there still needs to be some modifications to this, despite the fact that we all want an easier and less logistically challenging ramp-up for a BCL2 inhibitor.

The other one that was reported was Bgb-11417. Again, a same kind of theme here. While we’re trying to get an easier ramp-up, I don’t know if this ramp-up is any easier, frankly. It’s going over 8 weeks. And then they did another ramp-up where it was on a daily basis over an entire month, which is super complicated just for me looking at this, let alone trying to explain this to a patient.

So, they’re exploring these ramp-ups and maybe these will get easier with further iterations. This is early Phase I, dose-finding, and safety, et cetera. But, ultimately, what we see here is again, activity with this very potent BCL2 inhibitor as monotherapy and/or in combination. Very small numbers of patients treated, but they attain MRD-negative states in certain amounts of patients.

And overall, looks like a safety profile consistent with what we know with venetoclax-based approaches in heavily pretreated patients. So I think these are comparable drugs. Hard to start to try to differentiate these agents. Venetoclax has a huge head start and comfort level out there in the world. And clearly, long-term data and certainty around MRD-negative states, et cetera. And I do think because venetoclax is still just such a well-tolerated drug, it may a hard target to knock off as a preferred agent. But it’s exciting to see more research, exciting to see new agents and potentially how these might be able to differentiate themselves going forward.

Evolving data with subcutaneous epcoritamab for patients with Richter’s transformation and CLL

DR ALLAN: And then the last study here was just looking at some bispecific data in Richter’s transformation. Arnon Kater had reported 9 patients with CLL, relapsed CLL, being treated with epcoritamab, and showed a response rate of about 44% in these heavily pretreated, median prior lines of therapy, 6 prior lines of therapy. In this study here, we are seeing these are patients all with Richter’s Syndrome. And what’s exciting is that we don’t have a lot of good therapies after you progress, after front-line chemoimmunotherapy. With the role of CAR T-cells and now bispecifics and the advent of these, clearly the next logical step is to start to test them in Richter’s.

And here is a monotherapy approach in 10 Richter’s patients. Some pretty impressive responses. We see an overall response rate of 60%. The vast majority of those are complete remissions. And those patients who get complete remissions seem to have very durable disease.

The nice thing about bispecifics is that they don’t come with the toxicity profile that we see with CAR T-cell therapies, where we see — CRS is still something we need to monitor and look for, but we don’t see lots of Grade 3/4 CRS. We do not really see any of the ICANS stuff that we see with CAR T-cells. And ultimately, it’s a pretty safe drug and well tolerated. And something with epcoritamab we see this later onset of CRS in this third week, et cetera.

DR LOVE: So, what about bispecifics in, like, non-transformed CLL?

DR ALLAN: So we have a dearth of data. This EPCORE 1 had a CLL cohort. They have this Richter’s cohort as well. Arnon has shown — Dr Kater has shown 9 patients — I think 11 patients previously treated, and the data is okay. Again, we see responses. We see some CRs. But we’re still dealing with an inherently defective CLL T-cell and I think that’s one reason why responses with CAR T-cells, responses with bispecifics, may be a little less than what we’re seeing in other disease states, B-cell malignancy disease states, because the T-cell is not as severely defective in some of those entities. But I think there is a role for these drugs.

There’s good data that BTK inhibitors can, in fact, enhance the T-cell response and T-cell fitness and T-cell product, et cetera. Clearly, CLL being a disease that BTK inhibitors are very effective in, maybe that is a way to condition that T-cell environment to get better responses, et cetera.

But early data. I think it’s there. I think it’s going to be valuable. I do think we’re going to get these approvals soon in other histologies. And this data is a little bit lagging, just because these therapeutics are just so good. And these patients are disappearing on us that are even needing these drugs beyond BTK and venetoclax-based approaches.

DR LOVE: Yeah, but I am wondering, like follicular lymphoma. It’s like moving up fast, mosunetuzumab. I don’t know, it may be second-line therapy soon.

But I wonder though, when you think about the anti-CD20 issue with CLL versus lymphomas, obinutuzumab versus rituximab, maybe it’s the CD20 end of the bispecific that is the issue.

DR ALLAN: Yeah. I think CLL has a dim CD20; sometimes it can knock it out as you progress. And with BTK inhibitors, it’s known to knock down CD20 expression the first 6 months and then it comes back and it affects NK cell function and things like that. I think using the T-cell here is important, outside of just the other monoclonal antibodies that we use.

I think it’s a great question. And we’re going to have potential new approvals this year with more bispecifics coming into the space and DLBCL and follicular lymphoma. So it’s going to be exciting to see that. And I think it’s going to still be hard to use those types of drugs off-label in CLL, without this strong data just because it’s tough to get these drugs outside of their label. But I think this data is encouraging. And I do think there will be some relevance for these immunotherapeutic approaches into the future.

There were other agents that I didn’t bring up. I just wanted to bring up that BTK degraders are out there as well. They degrade the BTK protein and showed some very prelim data with the first one that’s out there, with about a 40% response rate in heavily pretreated patients. But some encouraging data there. And many other companies are producing those drugs as well. That’s something we’ll continue to see at future Congresses as well as that class of molecule BTK degraders.

DR LOVE: This concludes our program. Special thanks to Dr Allan and thank you for listening. This is Dr Neil Love for Oncology Today.