Ryan Topping (CCO): Hi, Matt. Hi, Lindsey. This is Ryan at CCO. How are you doing?
Dr. Lindsey Roeker (Memorial Sloan Kettering Cancer Center): Good, thank you. Thank you. Sorry for the delay.
Ryan Topping: Oh, no problem. Thanks to both of you for joining us for this. Yes, so I thought what we could do is just talk a little bit about the outline for this, and then kind of work off of that. We are hoping just to really have a conversation, talking about what you are thinking about in your practices in terms of BTK inhibitor resistance and how it influences your treatment decisions in first-line and beyond, or if it does.
So here is our format for the program. We are looking for about 30 minutes. It can be a little less or a little more, depending on how we end up talking. We are going to take what we get here, and we are going to make it into an audio podcast. So we will do some edits and turn it into a podcast, and then we will also take a transcript, edit that, and turn it into a text module with some slides that we will add in later based on what you talk about.
And so you can see our learning objectives here. I will not go through them all. They will be in our content outline. However, essentially, we are looking, as I said, to talk about BTK inhibitor resistance, how you think about it in terms of sequencing therapies, when and how you test for it, and what you do to overcome it when you find it.
Just a brief background to why we were interested in this. This is something that comes up in our educational programs, but we often do not spend a lot of time focusing on this. So we wanted to put together sort of a focused program, just looking at this as guidance for other practitioners.
[00:04:12]
So I have this content outline here. It is basically the one I sent yesterday. I turned some of these into questions. So maybe we can kind of go back and forth talking about these. What we had hope to do is have you both introduce yourselves and then just give a brief introduction to what we will be talking about. And then start with first-line treatment for CLL. Maybe we could talk a little bit about the therapeutic options, give a brief overview of efficacy and safety, and then dive into resistance. I am not sure you do this when considering first-line treatment, but one of the questions that we had is: Is there ever some kind of intrinsic resistance to BTK inhibitors? Is this something that you look for? Is this something that people should be looking for? How is it done? And then, of course, what, I assume, is maybe the larger question here, how to look at it when someone experiences progression of disease on a BTK inhibitor and what you do then?
So, yes, I would love to have your thoughts on this. And if you would like to add, or if there is anything we have missed in terms of how you think about this topic.
Dr. Roeker: Maybe we should start with kind of like, what are the tests you do before you start frontline therapy? Like, how do you think about genetic profiling of the disease so that we can get a sense of, like, cytogenetics, mutated IGHV or IGHV mutational status. Whether next-generation sequencing is indicated before frontline therapy is kind of a starting point. Because that is sort of like the serial testing that in many patients you do to help understand, over time, what mutations are developing. I do not know. What do you think, Matt? Maybe off-topic, but I think –
[00:06:39]
Dr. Matthew Davids (Dana-Farber Cancer Institute): I think that is relevant. Especially if we then kind of focus in on, like, how TP53 status and IGHV status may influence our choice of therapy between BTK inhibitor versus ven + obin right now.
Dr. Roeker: Yes. Totally. And in terms of, Ryan, can I ask a clarifying question? Are we looking for 30 minutes of content, or we are talking for 30 minutes, and you are editing it down?
Ryan Topping: Yes, we will edit it down. So you can talk over a little bit, and we will edit it down. It is not a hard and fast rule. I just wanted to give a bit of a guideline. So we do not talk for ten minutes and we do not talk for two hours.
Dr. Roeker: Okay. It is just, yes, good for us to have a sense of the detail we want to get into.
Ryan Topping: Yes. So I think 30 minutes as a goal would be great.
Dr. Davids: So I would add maybe a quick bullet on ven + obin, even though it is not the exact topic here, but I think it is kind of relevant just to lay the groundwork for what other treatment options are available. And then maybe also comment on BTK plus BCL2 regimens, especially since we expect one to be approved in the US pretty soon. And how that might affect resistance to BTK inhibitors, I think, is relevant. Okay.
And then my other thought was just in terms of the flow, probably the most important thing we could do is just kind of annotate as we go here, like, who is kind of leading which part of the discussion because maybe, like, Lindsey, you could kind of lead part and ask me questions and then vice versa. So it is not just like one of us the whole time, does that work for you?
[00:08:17]
Dr. Roeker: Totally.
Ryan Topping: Yes. That sounds great.
Dr. Davids: Yes. So for intros, do you want to go first, maybe, and then I will introduce myself? So, Ryan, can you just put that in so that we remember what we are talking about? And then do you want to maybe lead the questioning for the first part, Lindsey, on first-line treatment, and then I will lead the questioning on second-line and later?
Dr. Roeker: Yes. Totally.
Dr. Davids: Okay, great. And obviously, even if you are leading and asking the questions, feel free to jump in with your comments, too. I might kind of punt it back to you, too, and just be like, is that how you think about it, too, so it is more of a dialogue.
Dr. Roeker: Absolutely. Definitely.
Dr. Davids: Great.
Ryan Topping: Yes, I think that sounds great. Yes. And if there is anything we do not have here but kind of pops up during the discussion, we are happy to get into that as well. It is a bit of an open-ended forum for this one. We call them "cancer conversations", and it is really just an informal look at how you think about these topics in practice.
[00:09:39]
Dr. Davids: Yes, I think that is good. I think in that latter part, like, that last question, how should it be managed post-non-covalent BTKi? That might be a good opportunity to touch on BTK degraders, but also maybe immune-based therapies. What is the role of CAR T and maybe future role of bispecific antibodies, those sorts of things? Yes. And then I guess probably within the conversation, maybe especially in the second part, weaving in some of the data around specific resistance mutations and sort of, like, the patterns, how they differ between covalent and non-covalent BTKi? It is kind of implied in these questions. I am sure we will get to that, but I think that is important to cover.
Dr. Roeker: Absolutely. That can kind of tie into the first question, so, like, looking at BTK resistance, saying, like, there are a template or, ways to look for the canonical BTK mutation. However, we are also learning more and more about these non-cys-481 BTK mutations and then go from there. Does that seem reasonable?
Dr. Davids: Yes, that is what I was thinking. However, we should probably try to break it into small parcels. So I will ask maybe that first part and try to give a relatively brief answer, so that then I can kind of, what about for non-covalent BTKi? Because I am sure you can easily talk for ten minutes answering that, but I think keeping it more of a dialogue would be good.
Dr. Roeker: Absolutely.
Dr. Davids: And I will try to do the same in the first part. Yes.
[00:11:02]
Dr. Roeker: Yes. And then also at some point, we should talk about the emerging data about non-cys-481 mutations within covalent BTK-treated patients, which probably makes sense to into the second- or later-line therapy discussion, right?
Dr. Davids: Right, yes.
Dr. Roeker: Like, we are still learning more about that.
Dr. Davids: Yes, that is right.
Dr. Roeker: Okay, love this.
Dr. Davids: Yes, it is good.
Ryan Topping: Okay, so we are recording now. So I think we can just get started. I will put myself on mute. Obviously, it would probably be best just to flow through this, but of course, we can stop and start as we are not live or anything. However, yes, I will put myself on mute. And, Lindsey, whenever you want to start it off, we are good to go.
Dr. Davids: One more question also is: Are we going to be video recorded as well for this, or is it just audio?
Ryan Topping: Just audio. You can feel free to have the video off if you like.
Dr. Davids: Probably better to leave it on.
Dr. Roeker: Just leave it on. I mostly need to figure out if I can drink my coffee.
Dr. Davids: Yes.
[00:12:19]
Dr. Roeker: And then the other piece is, are you picking up any background noise? Because I am in clinic and there are people talking out there, so I just do not know if it is coming through.
Ryan Topping: I am not. Elliott, do we sound okay?
Dr. Roeker: Okay, cool. Great.
Ryan Topping: Okay, I will be on mute then. And please go ahead when ready.
Dr. Roeker: So, thank you so much for joining us today. Today we are going to be talking about a cancer conversation and optimizing the care of patients with CLL through a deeper understanding of BTK resistance. My name is Lindsey Roeker, and I am an assistant attending and CLL Program Director at Memorial Sloan Kettering Cancer Center in New York City.
Dr. Davids: And I am Matt Davids. I am the Clinical Research Director in the Division of Lymphoma at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School here in Boston.
Dr. Roeker: And we are thrilled to be chatting with you about BTK inhibitor resistance, how we think about it, and how we should use these data in informing our practice. So we are going to take it through kind of two different sections. The first is looking at first-line therapy for CLL. How do we think about BTK inhibitors in this setting, and then the second section will really focus on second-line or later lines of therapy, and how do we think about BTK inhibitor resistance in the relapse refractory setting.
[00:13:44]
So kick it off, let us think about our current options for patients with CLL who are needing their frontline therapy. Matt, when you are meeting a patient who is showing signs that they need to be treated, what kind of testing are you doing at that point, and how are you thinking about that approach?
Dr. Davids: Yes, I think that is a great place to start, Lindsey. We send a pretty comprehensive genetic profile before we start treatment on our patients. And this includes FISH testing to look for the characteristic cytogenetic abnormalities. In particular, we are looking for deletion 17p, which, as you know, is a high-risk form of CLL. Then we look at the IGHV mutational status, which we know can be either mutated or unmutated, with the former being a more indolent form of the disease and the latter the unmutated being somewhat more aggressive. Then we also send a next-generation sequencing panel at time of starting treatment. And that is mainly to look for TP53 mutation, which, when mutated, is another high-risk form of CLL. And as we will see as we talk about the different treatment options, particularly these high-risk abnormalities do influence the optimal choice of frontline therapy. Our next-generation sequencing panel does include a variety of other genes, which I would say are a little bit more niche right now in terms of their significance in practice. So I think if you are not seeing that much CLL, really just focusing on that TP53 mutation test is really the key one.
Dr. Roeker: Yes, we do the exact same thing at MFK. So we are looking at cytogenetics just like you said, and then IGHV mutational status. Our panel that we send does include BTK as a gene that is tested in that panel, though typically upfront, we are not seeing BTK mutations. That is typically something emerging on therapy. So for people who are ordering testing as a single gene test, TP53 really is that one to focus on.
[00:15:35]
And, Matt, when you are meeting a patient and talking to them about their options for their frontline therapy of CLL, how do you present these options and what features are kind of pushing you one direction or the other?
Dr. Davids: First of all, I do always like to mention clinical trials because we always have things that we can learn in CLL, even though we do have many effective therapies now. However, as I kind of focus in on the standard treatment options, it is really right now between two main options. So one would be continuous treatment with a covalent BTK inhibitor. And we are fortunate that we have three of these available now in CLL. We have ibrutinib, we have acalabrutinib, and we have zanubrutinib. And actually with acalabrutinib, there is an approval with obinutuzumab as well. So that is an option to consider. However, really, the idea with BTK inhibitors in the frontline setting is that we use them as a continuous therapy until time of progression or an unacceptable toxicity. And most of our patients do tolerate these drugs well, and can stay on them for many years with excellent efficacy. However, we do also have a time-limited treatment option with venetoclax plus obinutuzumab. It is a little bit more intensive to get started on this treatment involves the infusional component and then the careful monitoring for tumor lysis syndrome with the venetoclax in the first couple of months. However, at the end of the one year of treatment, patients go into remission most of the time, and can have a durable remission, often for several years without need for ongoing treatment.
[00:16:54]
And then I will just highlight that coming soon, in the near future, we are going to likely have a combination of one of the BTK inhibitors, probably acalabrutinib, with venetoclax, and this is going to be a time-limited regimen without the need for an infusional component. So it will be an oral regimen and probably about 14 months long, and will be a nice option also to consider for those patients who like time-limited therapy, but maybe do not like the idea of the infusional component.
Now, one thing maybe if I could ask you, Lindsey, to comment on is we talked about the molecular profiling in the first part, so how does that influence your thinking about these different choices?
Dr. Roeker: Absolutely. So there are a couple of things here. The first is these really are just different regimens. A continuous oral pill versus time-limited therapy that, like you said, has some logistical considerations, are two different strategies. They have not been compared head-to-head. And I think that is an important piece to highlight, that in our current practice landscape, we do not have data saying that BTK inhibitors versus venetoclax or obinutuzumab, one leads to better outcomes.
A lot of what we have done up to this point is relying on patient comorbidities, meaning what other medical problems do they have? Is one of these options truly better than the other? And then also patient preference. There are patients who do not at all mind the idea of an additional pill, a couple times a day, and there are patients who really are opposed to that idea and really would prefer time-limited regimen. So I think that in the current landscape, that really has been a consideration.
[00:18:32]
Looking at patients with higher-risk disease features, so those with TP53 aberrations, either deletion of 17p or a TP53 mutation, the data are probably strongest for continuous BTK inhibitors. So we had a dedicated arm of a clinical trial looking at zanubrutinib, showing us how effective that regimen is for deletion of 17p. We have had longer-term outcomes looking at patients with TP53 aberrations and seeing that patients do really, really well with these continuous BTK inhibitors.
This number of patients that were included in the venetoclax + obinutuzumab study who had TP53 aberrations was relatively limited, and those patients had a shorter, progression-free survival when compared to those who did not. Now, you are kind of comparing apples to oranges, right? Continuous drug versus time-limited therapy. And if a patient with TP53 aberration at some point is going to have a venetoclax-based regimen, one could make the argument that maybe doing that upfront might give you the best shot at time-limited therapy. However, that is obviously a point that a lot of people debate. And I think until we have head-to-head data, we are really not going to know which of those approaches really is better. So right now, a lot of it does depend on patient preference and as well as comorbidities. Is that kind of how you think about it, or do you have a different approach?
[00:20:04]
Dr. Davids: No, that is very similar to how I think about it. I mean, I think the other key piece of missing data right now in that question is: How effective is venetoclax + obinutuzumab when given a second time as a retreatment strategy? Because you can imagine, even though the initial PFS might be shorter with ven + obin in a high-risk patient, that if you could give it a couple of times, that it may end up being similar to a continuous BTK inhibitor, but with a lot less treatment because it is a time-limited therapy. So that is really one of the key questions that we are trying to answer now in clinical trials. However, I agree with you. Until we have that piece of data, then we really probably should prioritize continuous BTK inhibitors for the high-risk patients.
That being said, if I have a high-risk patient who has some very serious cardiovascular comorbidities, maybe they are already on it, coagulation. These are some of the factors that might tip me toward using venetoclax + obinutuzumab, even in the high-risk patient because if they run into trouble with a BTK inhibitor early on, then we really have not done a service to the patient. It is complex. As you intertwine all these different factors, a lot of the ones you mentioned in terms of patient preference and comorbidities, and then the genetic factors, really allows us to individualize the optimal treatment for individual patients.
Dr. Roeker: I think the addition of BTK inhibitor plus venetoclax-based regimen into the mix is going to, at least for some time, make it even a little bit more complex rather than simpler. So we had some data come out last year in terms of looking at BTK inhibitor plus venetoclax regimens. And who are the patients when patients are progressing after these regimens, what is effective afterward?
Matt, can you take us through that data a little bit? Because I think that is informative as we are figuring out the role of these regimens in early lines of therapy.
[00:21:46]
Dr. Davids: Sure. I think this is a key question around the resistance because one of the common questions I have gotten when I have talked about BTK plus venetoclax regimens is, hey, you are using your two best mechanisms. First, what are you going to do when patients progress? What we have seen so far is that nearly all patients will go into an excellent remission with BTK plus ven-based regimens. And a good example of that is the CAPTIVATE study where patients were treated with ibrutinib plus venetoclax for a fixed duration in one of the cohorts for 15 months, and then went into remission. About 70% of the patients still in remission, around five years of follow up.
And one of the things that was interesting that emerged from the ASH meeting this past year is that in the relatively small number of patients who did recur and required treatment, they responded well to either BTK inhibitor as monotherapy or to BTK plus ven again. Getting the same regimen a second time. Response rates were in the range of about 85%. We do not know yet as much about the durability of those remissions, but it certainly looks promising that even if we use our two best mechanisms first, as long as we do it in a time-limited way, we are not going to see the emergence of resistance mutations arising. And this has also been reported in a separate publication where they took the patients who progressed on the CAPTIVATE study, and they sequenced them for the mutations we will talk about in BTK, as well as BCL2 mutations which could confer venetoclax resistance. And they did not see any mutations in these patients who had recurrent disease after time-limited BTK plus venetoclax.
[00:23:09]
So I am very optimistic about retreatment approaches in CLL, and I think the whole profile of resistance is going to be very different from what we will talk about shortly, which is resistance to continuous covalent BTKi.
Dr. Roeker: Awesome. So I think what we are really talking about here is how effective these frontline regimens are. And we have continuous therapies, we have time-limited therapies on the brink of having even more options. However, when you are thinking about a BTK inhibitor and really looking at that as the frontline regimen for a patient, either because that is their preference or their comorbidities suggest that that is really the best strategy for them, how do you think about the BTK inhibitors that we have approved in the front line, and are there differences in how safe these drugs are that make you reach one direction or another?
Dr. Davids: So, you know, we have had ibrutinib now for over ten years in CLL. We have a lot of experience with the drug. It is really the drug that revolutionized the treatment of CLL. And so I give a lot of credit to the developers of ibrutinib for really helping to revolutionize the field.
However, that being said, we have known for a while now that there are some significant cardiovascular issues with ibrutinib, particularly dysrhythmias, hypertension, and even ventricular dysrhythmias in some cases. For a while now, we have had a sense that the more selective, newer BTK inhibitors like acalabrutinib and zanubrutinib have a more favorable safety profile than ibrutinib. And now, over the last couple of years, we have actually had two head-to-head studies that have read out that have directly compared these strategies.
[00:24:45]
The ELEVATE-RR study compared ibrutinib to acalabrutinib directly in the relapse setting one-to-one randomization. And the ALPINE study was very similar, comparing zanubrutinib to ibrutinib. And both of these studies showed significant safety advantages of the newer, more selective BTK inhibitor over ibrutinib, again, particularly when it comes to cardiovascular toxicities. However, I think it is really impactful also to look at things like discontinuation rates, dose reductions, and these all tended to favor the newer BTK inhibitor.
So from these direct studies, I think it is pretty clear that we should be using either acalabrutinib or zanubrutinib for our patients. I think the challenge comes in that we do not have a direct comparison of acalabrutinib and zanubrutinib. And so maybe I could put that one back to you and just maybe kind of expand on how you think about the differences between those two drugs.
Dr. Roeker: Yes. So these head-to-head comparisons were done in the relapse-refractory setting and our different patient populations. So I think it is really easy when you have an A to B comparison and an A to C comparison to then take those data and say, okay, well, let us compare B and C. However, I think there were some structural differences in those studies that makes that comparison faulty.
[00:26:00]
So when I am thinking about the profiles of these drugs, we, you know, saw slightly different rates of atrial fibrillation. We saw that hypertension was maybe a little bit different between these agents. However, I do not think that we can really utilize these data to fully say, okay, because this was better in one study than it looked in the other, we really should extrapolate to say, that is a head-to-head comparison. And in order to overcome that limitation, there have been a lot of these studies called myacs. It is an indirect comparison, and it is using mathematical modeling and some manipulation of the data to make them more comparable.
Now, there have been conflicting myacs, which is always a little bit challenging, depending on which data set we use, to say that either zanubrutinib is better than acalabrutinib, or acalabrutinib is better than zanubrutinib. In clinical practice, I am really looking at the patient in front of me and what I anticipate they would tolerate better from a side effect profile. There are some subtle differences that do kind of differentiate these agents, and those tend to be kind of the features that I rely on more heavily. However, how do you think about kind of these indirect comparison data?
Dr. Davids: Yes, I agree. I mean, I have been involved with some of these analyses, and I do think they have some value because otherwise, if we do not use these systematic ways to compare across the studies, we are just going to compare ourselves anyway. And so, there is some logic to how the myacs are developed. You are right that there has been some conflicting results. To me, that suggests that these drugs are probably more similar than they are different. We do see in practice some of the things that have emerged. For example, acalabrutinib does seem to have a higher risk of headaches. If I have a patient who is known to have migraine headaches, and we are trying to choose between a BTK inhibitor, I tend to lean towards an zanubrutinib. On the other hand, it seems like acalabrutinib has a little bit of a lower risk of hypertension, whereas at least in the ALPINE study, zanubrutinib had a similar risk of hypertension as ibrutinib. So if I have a patient already struggling with hypertension and I have to put them on a BTK inhibitor, all other things being equal, I kind of lean toward acalabrutinib.
[00:28:18]
So there are some of these subtle things that point us one way or the other, but I think they are both great drugs. It is great to have these options. I would say right now, we do have longer follow-up with acalabrutinib in the frontline setting, which makes me a little more comfortable using that drug in that setting. Whereas in the relapse setting with zanubrutinib, in addition to the improved safety profile over ibrutinib, zanubrutinib did have an improved efficacy profile over ibrutinib, which I find intriguing. So I find myself using more zanubrutinib now in the relapse setting. And I think as these datasets continue to evolve, those preferences may change. However, that is sort of how I am thinking about it now.
Dr. Roeker: Yes, perfect. And I also think that as we have been talking about this efficacy piece and how we think about these agents, I think it does make sense for us to spend a little bit of time on the addition of obinutuzumab to acalabrutinib, and for whom that is the right choice, and how are you thinking about that? Could you talk to us a bit about how you are incorporating obinutuzumab in combination with acalabrutinib in the frontline setting?
Dr. Davids: Yes, that is a great point because we have now Phase III data from the ELEVATE‑TN study that show a progression-free survival advantage of acala with obin for an initial six-month combination, followed by continuous acala as compared with acala just given as a continuous monotherapy. It is about a 16% absolute improvement in PFS at six years. So it does look significant, even though, in truth, that was a post hoc analysis in the study, and it is not a study that was really designed to look for a difference there, and there is no overall survival difference between those two arms of the study.
[00:29:49]
So with those caveats, I do sometimes have patients who really want to maximize their initial PFS from their frontline therapy. And in that discussion, if they are willing to take on the additional inconvenience and some additional toxicity with the obinutuzumab, I think it is very reasonable to use that combination regimen. I would say in practice, when I present that option to most patients, and then I also present ven + obin, if they are getting the obin anyway, most patients like the idea of a time-limited therapy and will choose ven + obin. And the patients who go with acalabrutinib-based regimens tend to like the simplicity of with a single oral agent and go with that.
So I have not had a lot of takers for acala + obin as a continuous treatment. I know you guys have had a clinical trial of acala + obin developing that as a time-limited therapy, which, I think, is really intriguing, but not an approved approach. So, yes, I think it is a really interesting concept to use the two together, but I would probably prefer to use it as a time-limited therapy if your data look good, eventually.
[00:30:44]
Dr. Roeker: Totally, totally hear it, and thanks for that. So now let us delve into the idea of BTK inhibitor resistance. So if you have a patient where you started a continuous BTK inhibitor in the frontline setting, and now their disease is starting to demonstrate evidence of relapse, how are you thinking about resistance in this setting? What kind of testing do you do? And let us start there.
Dr. Davids: So the first thing I would say is that it is very unlikely to have completely de novo resistance to a BTK inhibitor. In other words, like a primary refractory patient, especially in the frontline setting. I cannot say I have never seen it, but maybe once or twice in the many, many dozens or even hundred patients or so that I have treated in this setting. So I think if you are seeing some kind of resistance, primary resistance to a BTK inhibitor, you want to start thinking about other possibilities. Could this be a Richter transformation, for example? Should I be getting a PET scan to look for something else? Because it is just incredibly uncommon to see primary resistance to a BTK inhibitor.
Dr. Roeker: I agree.
Dr. Davids: Do you agree? Yes. I mean, a lot of that, I think, is because we do not tend to see the resistance mutations emerging on BTK inhibitors until much later. We do not think they are necessarily there at baseline, although that is a little bit controversial about whether there may be some mutations that are selected out. However, my hunch is that these are resistance mutations that occur in patients on the drug and develop on the drug in the majority of cases. So it is really not necessary to test for BTK mutation prior to starting treatment. You can assume that there is no BTK mutations that are clinically meaningful, at least.
[00:32:24]
I think the question comes up of when to test for resistance in a patient who is doing well on a BTK inhibitor, and then maybe starting to show some early signs of progression. And that is sort of the framework of how I think about it. So most cases, patients will do well for several years, and then often it will be the lymphocyte count starting to rise a bit, and they are feeling fine otherwise, or maybe they are having some lymph node growth, even if the counts have not changed too much. That is a scenario where I do like to test for a BTK mutation, not so much because I am necessarily going to change therapy right away, but it does kind of help provide early warning that I am going to need to think about other options.
And one other thing to mention is that there are some differences in terms of the activity of the covalent BTK inhibitors against various mutations. And, for example, in patients who develop the C481S BTK mutation, they can do well for a period of time on ibrutinib. The median in some of the studies is around nine months from time of detection of the mutation until time of actual clinical progression. Interestingly, with acalabrutinib, it has a lot less activity against C481S BTK, and this has been my clinical experience as well. I am not sure if it has for you as well, but just those patients who start to progress on acalabrutinib with a BTK C481 mutation tend to progress fairly rapidly and need to switch treatments pretty quickly. Is that something you have observed as well?
[00:33:40]
Dr. Roeker: Yes, absolutely. And I think that the classic teaching is if you are progressing on one of the covalent BTK inhibitors, that should confer across resistance across the class, which is a rule of thumb, I think, is a fair rule. If you are expecting that you are going to have a durable response to a different covalent BTK inhibitor if they have developed progressive disease on one, probably is not a realistic expectation. However, like you said, these drugs have different ability to bind to different mutations. So I think that is an interesting piece. And so, for this patient who has been on drug for a while and is showing this rising lymphocyte count or slight nodal growth, what is the actual test you are sending? Let us talk about the mechanics of testing for resistance. How do you do that?
Dr. Davids: Yes. So, for us, we do have an in-house NGS-based panel that is sequencing, actually about 90 genes or so. And one of those genes is BTKs. Another one is PLC gamma 2, which is another mutation that can occur in this context that we think confers resistance. And so, for us, it is our internal panel, but there are commercially available panels that can be sent. So if that is not something you have access to yet in your practice, I think it is worth looking into of how you can do that. Certain companies, like Foundation Medicine, for example, have these tests available. And again, I think it can be informative in terms of understanding why patients may be developing resistance.
That being said, and we may get to this, I do not know at this point that it necessarily influences my choice of next line of therapy, depending on whether there is a mutation there or nothing. I am not sure if that is the case for you, Lindsey?
[00:35:22]
Dr. Roeker: No, I totally agree with you. I think we are also learning more and more about what mutations are arising in different contexts. The mutation that we have known about for the longest is the cys-481 mutation. And cys-481 in BTK is the attachment, the covalent binding site for the covalent inhibitors. When I am talking to patients about this, I use a key analogy, and I say, in order for this key to work on your BTK, your lock needs to have a certain confirmation. And if your BTK changes the confirmation of your lock, all of a sudden, your key does not work. And I think that that is really the mutation that we understood first. That is one that just makes intuitive sense.
We are also learning more and more about how other mutations can develop, even with covalent BTK inhibitors. And a lot of that work has been kind of inspired by the idea, and that this is jumping ahead a little bit, with non-covalent BTK inhibitors, we have found these additional mutations, and now that we are looking backward toward what is happening with the covalent BTK inhibitors, we are learning that mutations can develop not just at the site of covalent binding, but also in other parts of BTK.
Dr. Davids: Yes, absolutely. Since you brought up the idea of non-covalent inhibitors, why not transition a little bit into sort of the second part of our conversation around sort of second-line and later lines of therapy? We have started a patient on a covalent BTK inhibitor. They are starting to progress. Let us say we send mutation testing, and there is one of the mutations we discussed that is present. So what are the treatment options now to help overcome resistance to first-line BTK inhibitors, and how do you think about using them?
Dr. Roeker: I think after a frontline BTK inhibitor, the FDA-approved regimen is a venetoclax-based one. So MURANO was the combination of venetoclax and rituximab in the relapse-refractory setting as a two-year fixed-duration therapy. It is worth noting that that study included few patients who had a prior covalent BTK inhibitor. So this has been up to this date, up to this point, a relatively under-studied group of people because just based on when these studies were done, not that many patients had had a prior covalent BTK inhibitor or had developed resistance to a prior covalent BTK inhibitor.
[00:37:57]
However, we do know that there is activity of venetoclax in patients who have progressed on covalent BTK inhibitors. We see that in clinical practice, we have retrospective data suggesting that that is the case. And in the relapse refractory setting, we could have an argument to be said that perhaps obinutuzumab is also a better antibody to pair with venetoclax. However, ven-based regimens do have activity, even when covalent BTK inhibitors have been used and patients have developed resistance.
We also have the FDA-approved option of pirtobrutinib, which is the non-covalent BTK inhibitor. Notably, that is approved for patients who have had two prior lines of therapy. So that approval really is looking in that double-exposed patient population. So often my second-line of treatment based on the approvals is a venetoclax-based strategy. Is that how you are thinking about it, or anything to add to that piece?
Dr. Davids: Yes, that typically is how I have thought about it. I think it is challenging, as you highlight, that we really do not have good prospective trial data to understand what type of venetoclax-based regimen to use in the post-covalent BTK inhibitor space. We also had some data with continuous venetoclax therapy in that setting, but that was from a trial of patients with a median of four prior lines of therapy, which was mostly chemoimmunotherapy. So that really does not apply too much to a second-line, post-covalent BTKi patient either.
[00:39:30]
So I have found in my practice that, in the absence of compelling data, I put together what, I think, is probably the most effective regimen, extrapolating from other studies, which is a combination of venetoclax with obinutuzumab. And instead of doing the one-year of venetoclax like we do in the frontline setting, I will often use two years of venetoclax in this relapse setting. Extrapolating from that MURANO data set, that maybe the second year is helpful, but we really do not know.
I think the potential to use pirtobrutinib in the second-line setting is intriguing. It did get a listing there in the NCCN guidelines, even though, as you point out, it is not technically approved there. So that would be an off-label use of second-line pirtobrutinib. However, you can imagine, and I have encountered this situation, patients who really like the idea of the convenience of a continuous BTK inhibitor in the frontline setting, and they like the idea of staying in the class and staying with a BTK inhibitor and not complicating things with venetoclax and antibodies in that second-line setting. So I think that is a nice option to have pirtobrutinib available there.
So we are seeing more and more pirtobrutinib being used now, either in the third-line or beyond, but now also in the second-line setting. And I think one of the things that has been interesting is we have seen yet a different pattern of resistance mutations arising on pirtobrutinib. And I know this is something you guys have also been involved with at Memorial Sloan Kettering. So maybe take us through a little bit about how resistance develops on non‑covalent BTKi.
[00:40:50]
Dr. Roeker: So the discovery in this space has been really interesting. We had these patients who were on the Phase I/II study of pirto that led to the FDA approval of this agent. And with progression on pirtobrutinib, this new pattern of BTK mutations has emerged. So there are a couple of different ones that we think about.
So there are gatekeeper mutations, which are the mutations that block the drug from accessing the pocket where it binds. We talked about the lock in BTK changes confirmation, and you cannot get the lock in, Here, it is like there is a cap over the lock, so you cannot even get your key near the lock to try to make it work. So that is a gatekeeper mutation.
Then we are also seeing this idea of kinase-dead mutation, suggesting that BTK is a kinase in our cells, and it is allowing for signaling by creating this chemical conversion through the kinase. There are mutations that actually take away that activity. So the kinase is not working. You are not getting those chemical reactions in BTK, yet you are still seeing downstream activation, meaning that the other pieces or the other parts of signaling are still happening. And we think that that is because BTK, in addition to having kinase activity, meaning this kind of chemical reaction activity, also has scaffolding activity, which means it is like a platform where other proteins can assemble and allow for signaling as a platform.
[00:42:40]
So we are seeing both of these types of mutations pop up on pirtobrutinib. I think the interesting piece is that now, looking backward, we are learning more that some of these mutations might actually also be occurring with covalent BTK inhibitors. Can you tell us a little bit about that, Matt?
Dr. Davids: Yes, I think that is really an interesting recent finding. We just saw a publication on the resistance mutation profile of the patients on that ELEVATE-RR study of ibrutinib vs. acalabrutinib. And although BTK C481S mutations were the most common, they also saw in that study a significant proportion of the patients progressing on acalabrutinib with that gatekeeper T474 mutation, which was pretty surprising and a little bit concerning in terms of whether those patients would then respond to pirtobrutinib, since that is one of the mutations that seems to confer resistance to pirtobrutinib.
So I think there are certainly plenty of patients on that BRUIN study who had progressed on acalabrutinib who did respond to pirtobrutinib. So that aspect is reassuring. However, the other one that is come up is also seeing L528W, that is the kinase-dead or kinase-impaired mutation, and that has even been reported in patients on zanubrutinib. Again, raising this question of whether those patients would respond to pirtobrutinib. I think it really highlights that there is a lot we need to learn here still.
[00:43:59]
One thing that, I think, is a really interesting development in the field is a whole new class of BTK inhibitors called BTK degraders. As we talk about how we might manage our patients who are progressing on a non-covalent BTK inhibitor, that is really one that comes to mind. Maybe tell us a little bit about how that fits with your lock analogy there, and how you are seeing them playing out in trials.
Dr. Roeker: Yes, so BTK degraders are this new class of drugs, and there are a couple in clinical development where the idea is that the drug is going in and actually getting rid of the protein. So rather than just inhibiting it, or changing its confirmation so that it is not working as a platform, it is just gone. And these are drugs that, based on our early looks at efficacy and safety, seem to be really effective and well-tolerated, even after patients have progressed on prior BTK inhibitors, covalent and non-covalent. So we are seeing activity there, and I think it is going to be an important class of agents moving forward.
I think the other piece to think about is what implications these findings are going to have on sequencing. Because as we were talking about, we do not have a ton of data to say sequence ABC is significantly better than ACB or BC, like, whatever iteration you want to use. And I think that thinking about how resistance developing on your current line of therapy might confer resistance to a future line of therapy and whether any intervention in the middle might actually impact that. So if you have developed a resistance mutation on a covalent BTK inhibitor, but then you use switch gears and use venetoclax, does that actually get rid of the clone that had that mutation develop? And those are data that we just do not have, and we do not know. However, I think it is an interesting hypothesis and highlights how much we need to learn in this space.
[00:45:58]
Dr. Davids: Yes, I agree. I would say my hunch is that venetoclax is not going to completely eradicate a BTK mutant clone. We have certainly seen data suggesting it can decrease the VAF and even make it to the point where it is not detectable. However, unless venetoclax is hypothesized to actually cure the CLL, my suspicion is that it is going to come back at some point. And that is okay. We have a lot of options now to treat these patients.
I would say it is also interesting that with the BTK degraders, we have already now just recently seen the first report of a resistance mutation to one of those degraders, which is an A428D mutation in BTK, which has also been seen with some of the other BTK inhibitors. So I think that interesting as well. The BTK degraders are probably going to have their own pattern of resistance that develops. However, as you suggest, potentially rotating around, these drugs may continue to buy time as we wait for additional mechanisms to be developed.
Maybe that is a good place to start to wrap up, as we think about the future of CLL therapy because probably eventually, some patients will move through all these lines of BTK inhibitor-based therapies and venetoclax. And one of the intriguing developments in the field over the last couple of years has been the development of immune-based therapies in CLL. I thought I might never see it, given that the immune system is defunct in CLL, and here we are relying on the immune system. However, there are a couple of different approaches that have been promising over the last couple of years. Maybe you could talk about those.
[00:47:22]
Dr. Roeker: Yes. We recently had the FDA approval of CAR T therapy, and I think that there is work to be done in that space. The overall response rate to CAR T in CLL is low, but we do see that the patients who achieve responses do have durable responses. So I think that will be a strategy that is important for the field, and particularly for a subset of patients who have higher-risk disease. However, I think that we are going to figure out how to use them better and better with time. So that is CAR T.
We also have bispecific T-cell engagers, which have shown, you know, great activity in other lymphomas. And we are learning about how to utilize these in CLL. So there are ongoing studies looking at bispecific T-cell engagers in CLL, both as monotherapies and in combinations with other agents. And I think that we will be able to see how these add in as well. And then there are other inhibitors that are also in development. So maybe not as immune-based, but we have additional targets in the B-cell receptor pathway that are being studied as well.
So this is a field with a lot of current options that are incredibly effective, a lot of emerging options, and I think that the future is bright for our patients and for the care of this disease.
Dr. Davids: Yes, I think that is a great summary, and I fully agree. It has been an exciting time in CLL research over the last couple of decades. I think it is going to continue to be so in the next decade and beyond. And hopefully, our conversation today has been helpful to allow the audience to have a deeper understanding of BTK inhibitor resistance in CLL, so that people can better manage their patients with this disease.
Thanks everyone for tuning in, and we hope you will join us for another program soon.
[00:49:16]
Ryan Topping: Great. Yes, that sounded great. I thought it really flowed well, and a really nice discussion of all the topics involved here. So I always ask. I did not hear anything, but was there anything that you felt you possibly mis-said, or would like to revisit? I did not hear anything. I thought it sounded perfect, but I always like to ask.
Dr. Davids: Yes, nothing on my end.
Dr. Roeker: I actually thought it was okay. Yes.
Dr. Davids: Yes.
Ryan Topping: Yes. Great discussion. So what we will do is put together the text and the podcast, and I will send those to you for a review, and you can let me know if there is anything you would like to adjust at that point. However, thanks again for a great discussion. I think this will really be helpful. It is very topical, and as we said, we do not have much education on this topic, so I think it will really be great.
Dr. Davids: Great.
Dr. Roeker: Beautiful. Thanks for having us.
Dr. Davids: Yes, thanks, Ryan.
Ryan Topping: All right, thanks to you both. Take care and we will talk soon. Bye-bye.
Dr. Davids: Thanks. Bye-bye.
Dr. Roeker: Bye.
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