Bruton Tyrosine Kinase (BTK) Inhibitors have recently changed the treatment of CLL, but the efficacy of first-generation agents has been limited by relatively high adverse event and treatment discontinuation rates. Acalabrutinib, a selective, next-generation covalent BTK inhibitor approved for the treatment of patients with treatment-naive and relapsed/refractory CLL/small lymphocytic lymphoma (SLL), is hypothesized to have enhanced tolerability vs first-generation agents. Join Dr. Jennifer Brown and Dr. Tara Graff in this engaging webinar as they discuss the clinical implications of recent data on the efficacy and safety of acalabrutinib for the treatment of CLL from ASCO 2021.
*Review the efficacy of acalabrutinib in treatment-naïve and previously treated chronic lymphocytic leukemia
*Review the safety and tolerability of acalabrutinib in treatment-naïve and previously treated chronic lymphocytic leukemia
*Integrate new data into the development of treatment plans for chronic lymphocytic leukemia
The content for this program has been independently developed by Clinical Care Solutions.
Jennifer Brown, MD, PhD: Hello, everyone. Welcome today to this Conversations in Hematology: How will the data presented at ASCO impact community practice? Today we’re focusing on 2 key abstracts in CLL. My name is Jennifer Brown. I’m director of the CLL Center at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School. And I’m joined today by Dr. Graff.
Tara Graff, DO: Hello, good afternoon. I’m Dr. Tara Graff. I’m a medical oncologist at Mission Cancer and Blood in Des Moines, Iowa, focusing on CLL and other forms of lymphoma. Thank you, Dr. Brown, I look forward to our discussion today.
Brown: Thank you. So first we have a polling question to start us off. How many patients do you treat in a week? 1) less than 50; 2) 50-70; and 3) is greater than 70. Well thank you for answering the polling question. We’ll dive right in.
Our first abstract is abstract #7500 – the first results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia.
These are the results of the long-awaited ELEVATE relapsed/refractory study, which is reported at full final analysis. There were no interim analyses, as it turns out. And this is a randomized trial, Phase 3 trial, comparing acalabrutinib to ibrutinib in previously treated CLL patients who had either 17p deletion or 11q deletion. The patients, as it turned out, had a male predominance, the median age in the mid-sixties. They had a median of 2 prior therapies. And 45% of them had the highest-risk 17p deletion with the remaining 60% to 65% having 11q. This is really a very high-risk, heavily pretreated patient population. The primary endpoint of the study is noninferiority by progression-free survival for acalabrutinib compared to ibrutinib. The study did meet its primary endpoint. The progression-free survival curves are, essentially, almost overlapping with a hazard ratio of 1. And this is at a median of 40 months follow-up with a median PFS of about 36 to 38 months. Now (2:42) but these are, again, heavily pretreated patients with high-risk cytogenetics, and I think the median PFS that we see in this study is about what we would expect from prior data. So the study establishes that acalabrutinib is similarly efficacious to ibrutinib. And having done that, there are then a serial set of secondary endpoints that were also evaluated. The first one was the incidence of atrial fibrillation, which was found to be superior with acalabrutinib, namely lower with acalabrutinib, with an incidence of 9.4% compared to 16% over the entire duration of the study. If we restricted this analysis to just patients who had no prior history of AFib, the difference was a little bit greater with a 6% incidence in the acalabrutinib arm versus 16% (3:33). And if you look at the cumulative incidence over time, overall the hazard ratio is about 0.5 favoring acalabrutinib. Then the next endpoints were to look at infections, which were similar in the 2 arms, no different, and Richter's transformation, which was also similar in the 2 arms – just a handful of cases in each arm – and then overall survival. Overall survival was also not significantly different, although there were somewhat fewer deaths on the acalabrutinib arm. When we look at the other adverse events – some of them, perhaps, less serious adverse events that nonetheless cause our patients a lot of problems, such as arthralgias, for example – those were lower in the acalabrutinib arm. Low-grade bleeding was also significantly lower, and this was true in the cumulative incidence group (4:25) as well, although the rate of major hemorrhage was roughly similar between acalabrutinib and ibrutinib. There were more headaches on the acalabrutinib arm, and we do know that this is a well-known side effect of acalabrutinib that happens early after drug initiation. Usually only lasts for a few weeks – at most a couple of months – generally responds to acetaminophen or caffeine. Generally, I find that counseling the patients about the headache really makes it mostly a nonissue, particularly the fact that it’s going to go away relatively soon. There was also increased cough in the acalabrutinib – not quite sure what that means. So, these data, I think, are very exciting. It’s a very mature follow-up in a high-risk relapsed/refractory population showing noninferiority of acalabrutinib, essentially similar efficacy to ibrutinib, but really a quite significantly improved safety profile in terms of the cardiac adverse events leading, as well as some of the adverse events that are just bothersome things like the arthralgias and the low-grade bleeding with infusions.
So that’s my summary of that slide. Dr. Graff, what did you think of the data?
Graff: So I was actually really impressed with the data. I think it was a long time coming. In community practice especially, a lot of doctors are very comfortable using ibrutinib. I, personally, use a lot of acala. But the one question that continues to come up is well, which one is better? Is one superior? And so I think this answers the question that, you know, both are very good drugs, both are very efficacious. So in terms of which drug is better in terms of PFS and overall survival, I think, you know, they’re both great. Where I think we see them separate – and I know this is very true in my practice, and I’m interested to see what you see, as well – like that, you know, with the cardiac AEs, or adverse events, this is significant. We have a lot of patients who are older; we know the median age of diagnosis with CLL is 70. So a lot of these patients are going to have preexisting hypertension, atrial fibrillation, and that’s really important when starting a BTKi and selecting which therapy is best. And I do believe this abstract and this study really does show that you know, acalabrutinib really appears to be favored in terms of better profile for the cardiovascular side effects. In terms of the headache, most of these patients, you know, the headache goes away in 5 to 7 days. And if you just talk to them and discuss that getting some caffeine in them, we can usually shorten that duration as well. So, I was really encouraged by this. I think it was a long time coming, and I was excited to see it play out the way that it did. Have you seen anything different in your practice, or what do you think about this? Brown: Yeah, I agree completely. You know, I’ve been working with acalabrutinib for a very long time now – since the Phase 1 study – and, to me, it has really shown a really marked improvement in terms of the tolerability profile compared to ibrutinib right from the beginning. We really have had very few, if any, cardiac events, and just sort of the general malaise and fatigue that some patients get on ibrutinib, the joint aches, that’s [crosstalk 7:54] absent with acalabrutinib. And that really makes a huge difference, I think, in quality of life for patients when you’re talking about staying on a drug indefinitely.
Graff: No, I completely agree (8:03). Even with ____ who are already on ibrutinib and switching them to acala, they seem to do very, very well, and a lot of those side effects go away. So I’ve been very pleased.
Brown: Yes, I agree. And, you know, it was interesting because some of the early studies – the Phase 1, the early noncontrolled reports – I think a lot of people were questioning is it really different. You know, we’re still seeing arthralgias reported, we’re still seeing various events reported, which of course, we are because these are high-risk relapsed/refractory patients [crosstalk 8:34] we’re now asking for all these symptoms, which we might not have done in the first trials with ibrutinib, right? And so, it did look like there were some of the side effects. But I think those of us who’ve worked with the drugs knew that you know, acalabrutinib was really better tolerated. And so having the randomized data that actually proved that is satisfying now to point out to the people who maybe didn’t have the experience and weren’t sure from the data.
Graff: No, I [problem 9:02] with that. All right. Well, let’s move on to another abstract that was presented at ASCO, which was also very favorable. So this was abstract 7509, which looked at acalabrutinib plus or minus obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve CLL patients. So this was based on the ELEVATE-TN trial. And this is the 4-year follow-up and one other key abstract addressing CLL. (So I’m going to take that line out – we’re actually just focusing on 7509).
So in this abstract, basically of the original ELEVATE-TN trial looked at acalabrutinib plus or minus obinutuzumab versus the obinutuzumab and chlorambucil in, like I said, treatment-naïve patients. This was a Phase 3, randomized controlled trial with about 535 patients, of which 70% had high-risk cytogenetics with 63% of those having unmutated IGHV and about 9% having a deletion 17p. So high-risk patients from the start in this treatment-naïve population. There was an interim analysis at 20.83 months, and at that time, acalabrutinib plus or minus obinutuzumab did demonstrate superior efficacy versus the chlorambucil and obinutuzumab. So this is the 4-year follow-up data at about 46.9 months. And the efficacy continued. The median PFS, at 46.9 months, was not reached in either the acalabrutinib monotherapy arm and the acalabrutinib plus or minus obinutuzumab arm. This held true in the unmutated IGHV and 17p-deletion patients as well. The estimated PFS at 48 months was 87% for the acala plus obinutuzumab arm and 78% for the acalabrutinib arm. And then the estimated overall survival at 48 months was 93% for the acalabrutinib/obinutuzumab arm and about 88% for the acalabrutinib monotherapy arm. The median overall survival was not reached. And in this study, at the 4-year follow-up, there was a trend towards significance for overall survival in the combination arm with the acalabrutinib and obinutuzumab. So that is really encouraging that as time went on, the efficacy – whether you’re using acalabrutinib monotherapy or in combination with the obinutuzumab – continued. The overall response rate was 96% for the acalabrutinib plus obinutuzumab, 89% for the acalabrutinib monotherapy arm, and then 82% for the chlorambucil/obinutuzumab arm. Over 26% of patients achieved a CR with the acalabrutinib and the obinutuzumab. So that’s pretty significant. The DC rate – or the discontinuation rate – over time, about 25% of patients discontinued therapy mostly because of adverse events and not because of progression of the disease, which is encouraging. And this was pretty even in all of the groups. Actually, about 12% of the patients discontinued on the acalabrutinib/obinutuzumab arm, about 12.3% in the acala arm, and then actually more, about 14%, in the chlorambucil/obinutuzumab arm. And again, the progressive disease at 4 to (12:45) 6 months was really low – 4.5% of patients discontinued the drug due to progression of disease in the acalabrutinib/obinutuzumab and 7.8% in the acalabrutinib monotherapy arm. So, over time, the acalabrutinib monotherapy or in combination with obinutuzumab maintains its efficacy with its tolerability. So this was really encouraging knowing that these patients, over time, continue to do well. So I was very pleased with this update, and I think it shows that we, you know, have really good treatment for our patients whether in the treatment-naïve population or in the relapsed/refractory, as we saw in the last abstract. So that was really good.
So let’s go on to some discussion. So, Dr. Brown, were you encouraged by this to show that not at interim analysis, this data looked great, but now at nearly 47 months, we’re continuing to see this trend with the PFS and the overall survival favoring the acalabrutinib monotherapy or in combination with the obinutuzumab?
Brown: Well, absolutely. You know, I don’t think there was too much doubt that the PFS would favor the acalabrutinib arms over obinutuzumab/chlorambucil. So, I think, that is maybe less interesting to be than the absolute PFS numbers of 87% with the acalabrutinib/obinutuzumab and the 78% with the monotherapy at 4 years, which are really remarkably high. And then, another point that I was really interested in seeing in these data was whether the apparent advantage of adding the obinutuzumab – that we saw at the interim analysis – was still holding up. Because, you know, with ibrutinib and rituximab, we had 2 randomized trials showing no benefit of adding the rituximab to ibrutinib at all. And then we never had head-to-head data adding obinutuzumab to ibrutinib. We just had iLLUMINATE, which was the single-arm trial. So it was really hard to interpret what the obinutuzumab added to ibrutinib or any BTK inhibitor would really make any (14:52) difference. I think this data actually really suggests that it does. There’s almost a 10% improvement in PFS adding obinutuzumab to acalabrutinib. And then, of course, it could be related to the acalabrutinib being a more specific inhibitor and not affecting other ITK, for example, would inhibit the efficacy of the antibodies. [problem 15:12] also is probably related to obinutuzumab being a more potent antibody compared to rituximab. I think it’s really quite interesting, and that is starting to change my practice where I am, potentially, going to give the obinutuzumab in combination with acalabrutinib. Whereas I haven’t really ever given antibody together with a BTK inhibitor outside of a clinical trial very much until now increasingly…initially with the interim analysis, I started to do it some. But I think these data here are really holding up. The other thing was that the interim analysis it was only really the mutated IGVH patients who were benefiting from the obinutuzumab but here, also, the unmutated. And that was sort of emerging late, which was very interesting, and not really sure why that would be. But it’s interesting.
Graff: What I think [problem 16:00] have that younger ___ with a high tumor burden and, you know, poor cytogenetics, you know that you have this combination regimen with the acala and obinutuzumab, which is going to work, and it’s going to have excellent, you know, 96% overall response rate that’s pretty impressive. And here you’re not having to use any chemoimmunotherapy at all, and we’re using it just with targeted therapy and anti-CD20. So I think that really shows that we’re evolving so much with CLL and offering our patients, you know, great treatment options. So I was very, very encouraged by that as well.
Brown: The CR rate and the undetectable MRD rate in the acalabrutinib/obinutuzumab arm at this 4-year follow-up were pretty impressive to me, as well. I think the CR rate was about 30%, and the undetectable MRD was 38%, which is really striking for a BTK inhibitor where we don’t usually see CRs or undetectable MRD.
Graff: No, I agree. Well, thank you for that.
Brown: I suppose a question is how do you feel about the fact that the obinutuzumab/chlorambucil was used as the control arm? Does that bother you compared to say if they used bendamustine/rituximab? Or you’re find with the data as they stand?
Graff: It seems to be the gold standard in all of our trials. I think it would be good to see a different comparison arm when we’re looking at these different combination therapies, monotherapies. But we seem to always, you know, it seems to be our default is the obinutuzumab/chlorambucil or chlorambucil arms. I’m still very encouraged by this; it doesn’t really change my opinion or my selection of care. But I do think it would be nice to do, you know, as move forward with more clinical trials and starting to compare these agents to other combination therapies, that seeing I guess more widely used, you know, say bendamustine/Rituxan would be, you know, I think would be interesting. I mean, obviously, we did that with ASCEND looking at acalabrutinib monotherapy versus bendamustine/Rituxan/idelalisib/Rituxan. But that, again, was in the relapsed/refractory setting. So I think seeing something like that in the treatment-naïve population would be worth looking at. I don’t know, what do you think?
Brown: You know, I think it’s a better comparator. I think it hasn’t been used as much because the PFS is, obviously, a lot longer.
Brown: Zanubrutinib their frontline study is, actually, versus BR. Hopefully, we’ll see some data from that relatively soon. Also, acalabrutinib has an ongoing registration trial with time-limited acalabrutinib/venetoclax or acalabrutinib/venetoclax/obinutuzumab, and those are compared to chemoimmunotherapy either FCR or BR depending on the age of the patient. So, they do have a series of studies that include other comparators. It doesn’t really affect my view of the data with the acalabrutinib arm.
Graff: No, I was impressed, and I’ll continue to use other monotherapy or combination depending on the patient. It’s always a very much a personalized selection. But I think this holds true that, again, we have so many great options that are available (19:31) for patients.
Brown: Yeah, and that brings up the point that many of my patients who are interested in BTK monotherapy are not necessarily interested in coming to the clinic a lot. So they may not be the ones who want to come for obinutuzumab, right? And so then, you know, how much do you push them? I think that depends on their prognostic factors, their disease burden, their age, those issues.
Graff: COVID has certainly thrown a wrench in the whole anti-CD20 treatments, as well, so that’s just one more thing to sort of add to the array of the complexity of these patients.
Brown: Exactly. So I suppose we can move on to the Q&A. Please submit your questions. We have one, so far, we can get started with, but it would be great if we had a few more. We have a question how meaningful will these data be – I think referring to ELEVATE relapsed/refractory – since ibrutinib is now used frequently early in disease course? What do you think?
Graff: Well, I mean, I think this data…I mean it’s very meaningful. I know that ibrutinib is up there, obviously. But we just saw here based on the acalabrutinib, you know, what I just presented in 7509, that acalabrutinib monotherapy can be used in early in the disease course as well. So I guess the question that will people be selecting acalabrutinib more than ibrutinib? I would say if they’re looking at the cardiovascular side effects and possibilities, I would say that acalabrutinib will probably start getting used and get some more attention versus ibrutinib. Again, though, it comes down to what people are comfortable with and what they’ve always done. And we continue to see that trend, as well. But I think if people really look at these abstracts, we’ll see that acalabrutinib is much more tolerable and just as efficacious as ibrutinib.
Brown: Yeah, I think it gets actually to a study design question, too, right? So we have proof of equivalence in this pretreated, relapsed/refractory, high-risk population. Are we willing to generalize that to frontline patients? Personally, I think I am that at least there’s equivalence. Although, I think that if there were a different study design, it’s possible that the results could be somewhat different. And you could argue it either way. So if you use the lower-risk population, maybe you’d be more likely to see an efficacy difference if, say, acalabrutinib were more effective than ibrutinib, and that’s obscured in a harder to treat population. Alternatively, you could say maybe you should see it in a high-risk population; and if you don’t, you’re not going to see it anywhere. We don’t really know, but that’s the study design we have. We’re going to get really more than one head-to-head trial. It’s interesting because zanubrutinib’s head-to-head trial chose to use a sort of all-comer relapsed/refractory population, and their enrichment (22:39) for the high-risk disease is much less. And so, that data’s still very immature. It’ll be interesting to see how it matures and how we can’t really compare exactly – the studies are very different. But it’s just an interesting set of choices, the implications of which we don’t know for sure. But I’m just happy we have a head-to-head trial with all these drugs.
Graff: I know, right. Well [problem 23:02] with that RESONATE-2, we have a 7-year follow-up. And with acala, it’s a younger drug, so we have a 4-year follow-up. So ibrutinib has been around longer. So I guess I’m really happy with what we do have, but you can’t…again, ibrutinib’s a little bit older and has been around longer. It’s going to be interesting to see what zanu does. But we have great choices. And again, I’m just very encouraged by that.
Brown: Absolutely. Looks like we have another question – what about rituximab as the monoclonal antibody with acalabrutinib? I don’t think we have any data at all. You know, my view is that I do think obinutuzumab is a more potent antibody in CLL regardless and that that was shown by the CLL11 trial head-to-head, admittedly, with a poor backbone agent, chlorambucil. But still, the difference in progression-free survival was quite significant, as was the potential difference that we…we usually see better CR and undetectable MRD with obinutuzumab compared to rituximab [cut out 24:10].
Graff: Right. And, you know, rituximab was paired with ibrutinib we didn’t really see it do a whole lot. Now is that because of the ibrutinib? You know, who knows, we don’t really know that. But I agree with you – I think the obinutuzumab has proven to be more efficacious in this population. So I think that’s what we’ll continue to do. Should we go on to the next question? What are your thoughts on other agents in this class such as the pirtobrutinib, in which the data is less mature but seems compelling? So what do you think about this? This is, obviously, for patients who have maybe resistance to ibrutinib or acalabrutinib. How do you feel about this?
Brown: Right, so I think pirtobrutinib is very, very promising. And just to set up the landscape, so everyone stands. So we have the covalent BTK inhibitors – ibrutinib and acalabrutinib or what we mostly are focusing on today. Zanubrutinib is coming along, also, and recently had a positive registration trial. And those are all covalent inhibitors. They likely share a similar mechanism of resistance, which is a mutation of the cysteine 481 residue in the protein to serine or some other amino acids that can’t bind covalently. And so pirtobrutinib was developed in patients who were previously exposed to covalent BTK inhibitors. It’s noncovalent, it doesn’t bind permanently. So it’s really almost a different class of drug, even though it hits the same target. And so the data [cut out 25:54] are really very encouraging. And I’ve been involved in the trial, so I do have personal experience with the drug. We are seeing very rapid deep responses, and we’re seeing them really from the earliest dosing level of pirtobrutinib. They’ve treated now over 350 patients with also a remarkable safety profile – almost no Grade 3 or 4 adverse events at all. I think in terms of the efficacy data in the patient population, the follow-up is still pretty short. The response rate looks good, and they do have at least some heavily pretreated patients who’ve had covalent BTK and venetoclax on the trial. But it’ll be interesting to see as the data mature, how the durability of response holds up in the various patient populations, the ones who’ve come off covalent BTK inhibitors due to (26:40) adverse events, the ones whose disease has progressed, the ones whose disease progressed on both covalent BTK and venetoclax. So the question, then, there’s a different activity in this resistant population. But I think that the developers of the noncovalent drugs, including pirtobrutinib, potentially might want to move them earlier in therapy, and that we really don’t know yet, I think. We don’t know enough about the mechanisms of resistance to pirtobrutinib itself and how those might occur if we use it earlier. But it’ll be really interesting.
Graff: Right. I guess (27:16) is building on that is that we’re just expanding our repertoire of drugs, which I just think is…you know, we’re really going to have CLL as truly a chronic disease and giving them the same life expectancy, hopefully, as somebody who doesn’t have CLL. Because we are going to have some really different options and being able to come at them from different angles. So I just think it’s one more addition that gives our patients hope and gives them the best possible treatment. So, it’s encouraging.
Brown: Yeah, to let them stay with BTK inhibitors for potentially a lot longer – almost like maybe another line of therapy…
Brown: …you know, in addition to BTK and Bcl-2. So that could add years…
Brown: …which is great.
Graff: Definitely. Any other questions out there?
Brown: No, looks like we’re good to go. So we have a few final poll questions for everybody. Poll 2: Was this content related to your practice? Thanks for answering that one.
Poll 3: Did you like the presentation format of this ClinicalXchange?
Poll 4: Would you recommend viewing a ClinicalXchange to a colleague?
So thanks for answering those questions. Thank you, Dr. Graff, for this interesting discussion, and thank you to the audience for listening. I hope everyone enjoyed the Xchange and has a great rest of your day.