Activity Transcript

Segment 1

Jennifer A. Woyach, MD: Hi, my name is Jennifer Woyach. I'm a professor of medicine at the Ohio State University in Columbus, Ohio, in the United States. I'm going to start today by providing you a review of the latest data of Bruton tyrosine kinase (BTK) inhibitors, in relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

So, let's start with the phase 1/2 study of acalabrutinib monotherapy, in patients with relapsed/refractory, CLL. This is the final results of this trial with over 4 years of follow-up. They, too, have a median follow-up at this point of 53 months, in patients up to 7.4 years of therapy. We have seen now on this trial, a medium progression-free survival of 66 months, which is pretty similar to what we've seen in the phase 3 setting with the pivotal ASCEND trial, which was the one that led to the FDA approval of this agent.

And with even very long follow-up of patients, people continue to tolerate acalabrutinib extremely well. We see a rate of atrial fibrillation of 9% at this time point. So, it certainly increased from those earlier follow-up times, but still relatively low for this patient population. Major bleeding events were similarly low at less than 5%. And many of the side effects that occur early on in therapy become lower in grade, and lower in frequency, over time.

One of the very exciting abstracts at [the] American Society of Hematology (ASH) [conference] this year, is a late-breaker abstract, which is the results of the ALPINE study. This study is a phase 3 head-to-head comparison of zanubrutinib vs ibrutinib in patients with relapsed/refractory CLL and SLL. And this is the final analysis of these data. So, this has been presented before with regards to the overall response rate, and here we're seeing the final progression-free survival (PFS) analysis. Here, the median follow-up is 29 months. And this study was actually designed as a noninferiority study for overall response rate initially. And so, that was the primary endpoint with other endpoints looking at progression-free survival, looking even for superiority of zanubrutinib over ibrutinib. And, actually with this follow up, we continue to see an advantage in terms of both overall response rate and progression-free survival, for zanubrutinib compared with ibrutinib.

We also see a significant difference in terms of atrial fibrillation, which is what we expect from many of the other studies of zanubrutinib and CLL, as well as other malignancies. With this time point follow-up, atrial fibrillation rate is 5% for patients treated with zanubrutinib, compared with 13% for patients treated with ibrutinib. And that 13% is pretty consistent with what's been seen on other studies with this length of follow-up. We do see, in addition to atrial fibrillation, overall cardiac events were lower with zanubrutinib compared with ibrutinib. However, hypertension is relatively similar between the 2 drugs. They also saw relatively similar rates of other side effects, including cytopenias.

And at 24 months, progression-free survival of zanubrutinib was 79.5%, compared with 67.3% with ibrutinib. This is actually a little lower than we expect to see with ibrutinib, but this time point, but it has been the standard for this study, as it has been reported all along. Even patients with del(17p) and TP53 mutations, had a superior PFS with zanubrutinib compared with ibrutinib.

So, our next abstract is a secondary analysis of the ELEVATE-RR study. And so, this trial was a head-to-head comparison of acalabrutinib vs ibrutinib, in patients with relapsed/refractory high-risk CLL. And so, high risk was defined as either del(11q) or del(17p). And del(11q), of course, subsequently is found to not be that much of a high-risk factor when looking at BTK inhibitors, but of course that wasn't known at the time the study was designed.

So, this data that was presented here, like I mentioned, was a post hoc analysis, and it was looking at adverse events using a novel statistical method, which looks at both the grading of the toxicity and the frequency of the toxicity in the population, but also the length of time the toxicity occurs. Which is potentially a good way to look at toxicities in continuous treatments that are given for long periods of time.

So, here we see, as has been shown previously in the ELEVATE-RR study, there certainly are lower risks of some of the key adverse events, including atrial fibrillation and hypertension. This novel method is expected to be good when looking at some of those really common toxicities in the general population, things like musculoskeletal things, headaches, diarrhea, things like that. We see overall, the adverse event burden with acalabrutinib is lower than ibrutinib. And for specific side effects of atrial fibrillation, hypertension, bleeding overall and musculoskeletal events, the adverse event (AE) burden is higher with ibrutinib. The AE burden of diarrhea and headaches was actually higher with acalabrutinib. And that's actually also interesting, because the frequency of diarrhea was a little bit less with acalabrutinib than ibrutinib. So hopefully, this is a design that catches on when looking at other trials of continuous drugs, compared head to head.

So now, let's move into the noncovalent inhibitors, and pirtobrutinib is also a very exciting drug at this ASH meeting. And so, one of the trials that was presented, or one of the data pieces that was presented, is additional patients treated with pirtobrutinib on the phase 1/2 BRUIN study. And so, these are patients with relapsed/refractory CLL. Now there's a total of 247 patients on this trial. Patient characteristics are what you would expect for a fairly highly refractory group of patients with CLL. Median age is 69 [years]. By design, a 100% of patients had prior BTK inhibitors, and 41% of patients also had prior venetoclax. There were a handful of patients treated with chimeric antigen receptor (CAR) T cells, and even with allogeneic stem cell transplant.

They looked at baseline of patients who had C481 mutations, conferring resistance to the covalent BTK inhibitors, and that was seen in 38% of the patients. They also had a handful of patients that had PLCG2 mutations, although actually which mutations, those are not known. Frequency of del(17p) and TP53 mutation was relatively high, as well, with 28% of patients having both del(17p), and a TP53 mutation. And 42% having complex karyotype. Most patients did discontinue their prior BTK inhibitor for progressive disease, although there were a few who had actually come off for toxicity or other reasons.

So, the efficacy of ibrutinib in this patient population, is what we would expect given the previous iterations of this data set. The overall response rate now is 82%, so that actually has gone up with longer follow-up. And there's even a couple patients who have achieved a complete response. You can see with the waterfall plot that responses are seen universally, even among patients who discontinued their prior BTK inhibitor for progression, those that had received a prior B-cell lymphoma (BCL2) inhibitor, as well.

One of the most important things about this data cut is, we now see a median progression-free survival for this drug, and it is 19.6 months, which is actually fairly similar to what we see with the median PFS in patients who were those double-exposed patients. People who had been on a BTK and a BCL2 inhibitor, where the median progression-free survival was 16.8 months.

When looking at subgroups, really overall response rates were high among all patients with potentially a trend towards those patients with PLCG2 mutations having a lower response rate.

PFS looking at certain patient subgroups. Really, the PFS is actually the same for pretty much every subgroup I had mentioned already, those double-refractory patients, patients with C481 mutations had just as long of a remission as those without. del(17p) and TP53 mutation patients tended to do just about as well. Those patients who actually were the pentarefractory, so who had received prior BTK inhibitor chemoimmunotherapy, BCL2 inhibitor, and phosphoinositide 3 (PI3)-kinase inhibitors. Those patients did have a little bit shorter progression-free survival, as you might expect.

Safety profiles, pirtobrutinib continues to look outstanding with relatively low rates of toxicity in general, and especially very low rates of grade ≥ 3 toxicity. We see things like fatigue, cytopenias, diarrhea tend to be the most common, and most of those are low grade.

Next, we have the noncovalent inhibitor nemtabrutinib. So, this is a follow-up of the phase 1/2 Bellwave-001 study. This study has 57 patients treated at the phase 2 dose of 65 mg daily. They saw an overall response rate of 56%, and a median progression-free survival of 26 months for patients with CLL and SLL.

This drug, as well, is relatively well tolerated. Dysgeusia, fatigue, and cytopenias are the most common toxicity. Atrial fibrillation was reported in 4% of patients, and hypertension in 30%. About 13% of patients discontinued treatment because of toxicity. So, I think these data continue what we've seen previously with nemtabrutinib, and CLL and SLL, with some promising early clinical data, a relatively good toxicity profile, and certainly justifying further investigation of this agent.

Thank you very much for participating in this activity, and please continue on to view the next chapter, where Dr Toby Eyre and I will discuss the clinical impact of the data I just presented.

Segment 2

Toby A. Eyre, MD, MBChB, DipMedEd, MRCP, FRCPath: Hello, my name's Dr Toby Eyre, and I'm a consultant hematologist and lymphoma specialist from Oxford in the United Kingdom (UK). And I'm pleased to join Jennifer today to talk about the clinical implications of the data you have just presented, Jennifer.

So to begin with, we've now got the ALPINE study and the ELEVATE-RR study. What role do you think ibrutinib has now moving forward in relapsed CLL?

Jennifer A. Woyach, MD: Yes, that's a really, really important question, and I think one that we're probably not entirely sure about yet. So certainly we've seen with 2 head-to-head trials now with both acalabrutinib and zanubrutinib, that toxicity of the second-generation BTK inhibitors is better than what we see with ibrutinib. And now we have the ALPINE data showing that actually progression-free survival is better with zanubrutinib compared with ibrutinib. I think this really limits the role of ibrutinib, especially with specifically the data and relapsed/refractory CLL. There's probably a few patients who could still benefit from the once-a-day dosing of ibrutinib, compared with twice a day with the other agents. But I think we'll just have to see with longer follow-up from some of these studies whether they're looked like there are other groups of patients who have significant benefit. Any other thoughts?

Dr Eyre: Yeah. No, I absolutely agree. I mean, I think this really solidifies the second-generation BTK inhibitors as the new standard-of-care options in relapsed CLL when the agents used as monotherapy. Of course, ibrutinib may well be developed in combination.

Dr Woyach: Yeah.

Dr Eyre: But for now, certainly the second-generation BTK inhibitors seem to be the most likely to be used moving forward. I suppose some of the dose attenuations with ibrutinib are perhaps well known, and people have experience with them. So, if that's necessary in certain patients, that may be a reason to give patients ibrutinib, but I think that's becoming less and less likely moving forward.

Dr Woyach: Yeah.

Dr Eyre: So we've got now acalabrutinib and zanubrutinib as approved options in relapsed CLL. How do you think you might pick between the 2 given the ALPINE and ELEVATE-RR studies?

Dr Woyach: Yeah, again, a really difficult question to answer. I think it's really intriguing to see that one of the covalent BTK inhibitors seems to have a superior progression-free survival to ibrutinib. Whereas, you might expect actually that all 3 of those are going to have pretty similar efficacy, especially with what we saw in the ELEVATE-RR study previously. Certainly, both acalabrutinib and zanubrutinib are very active drugs, produce durable remissions in the majority of patients. Zanubrutinib seems to have a lower rate of atrial fibrillation. I might use that preferentially in patients who have risk factors for a-fib. However, on the flip side of that, acalabrutinib seems to have a lower risk of hypertension. And I think especially if you're planning to continue the therapy for many years, that's certainly a consideration. So for patients with preexisting hypertension, I may choose acalabrutinib over zanubrutinib. Anything else that you think about when you're trying to decide?

Dr Eyre: Yeah, I think that you've mentioned the key things there. I mean, I think you would probably just use whichever you think is most appropriate for your individual patient in front of you. It's hard to talk about superior efficacy between the 2, given the different natures of the 2 studies.

Dr Woyach: Right.

Dr Eyre: But I think they're the 2 key things. I suppose occasionally we see headache with acalabrutinib, and then maybe the occasional patient with a, I don't know, history of bad migraines, or something that might be anxious about using it. So, I think patient-related factors, I think really will play into the choices going forward.

Dr Woyach: Yeah, I definitely agree.

Dr Eyre: So you've presented the data on pirtobrutinib now, the reversible noncovalent BTK inhibitor. Where do you see its role moving forward in CLL in terms of the treatment pathway?

Dr Woyach: Yeah, what we've seen so far is all patients who had previously received a covalent BTK inhibitor. And I think right now that seems to be the logical place to use the drug, because we know that it works in that setting. With the resistance mechanisms that have been identified so far, it is not very clear that you could ever sequence a covalent BTK inhibitor after pirtobrutinib, which makes me hesitant to think about the sequence where you might use pirtobrutinib first. Although, there actually are studies that are going on right now that are looking into that as a potential option, too.

Dr Eyre: And we've got some patients from the BRUIN trial who actually were covalent BTK naive. We didn't . . .

Dr Woyach: That's right.

Dr Eyre: . . . see them at this ASH . . .

Dr Woyach: Yeah.

Dr Eyre: . . . but in time, hopefully we'll see the follow-up of those patients, and that might give us an idea as well about resistance mechanisms, potentially.

Dr Woyach: Yeah, absolutely. Because the PFS we've seen is actually relatively short. So only 19.6 months. Of course, a very highly refractory group of patients. So then it's really going to have to lengthen significantly, if that's going to be to covalent inhibitor in the earlier line of therapy setting.

Dr Eyre: Do you think mechanistically, we could see a scenario where we use a noncovalent BTK inhibitor first, and then use a covalent BTK inhibitor? Can you see there being efficacy of the covalent BTK inhibitors after noncovalent?

Dr Woyach: I don't think so. I mean, of course, that sequence never has never been tried clinically. With the in vitro studies that have been done, I don't believe it looks like the covalent inhibitors would have activity after the mutations that have tended to occur most frequently with pirtobrutinib. I think a big question though is, are you going to see these same mutations if you look earlier in patients? So maybe people who had not had 5 prior therapies are not going to actually develop these same mutations, and that would really change the conversation.

Dr Eyre: Yeah. And also the randomized trials that are ongoing will of course dictate our availability and use of the agent moving forward.

Dr Woyach: Yeah.

Dr Eyre: Great. Well, thank you.

Dr Woyach: Thank you.

Dr Eyre: Thank you for joining. Please continue to the next chapter, where I will discuss the latest data on BTK inhibitors in relapsed/refractory mantle cell lymphoma.

Segment 3

Toby A. Eyre, MD, MBChB, DipMedEd, MRCP, FRCPath: Hello. Let me continue by providing you an updated review of the latest data of BTK inhibitors in relapsed/refractory mantle cell lymphoma.

So we've heard from Jennifer about the CLL patients treated in the BRUIN study with the noncovalent BTK inhibitor pirtobrutinib, and there's been an important update for the mantle cell lymphoma cohort within this study. So there have been additional patients and longer follow-up reported. Pirtobrutinib continues to demonstrate promising and durable efficacy in a heavily pretreated group of relapsed/refractory mantle cell lymphoma patients who have all been treated with a prior covalent BTK inhibitor and have received a median of 3 prior lines of therapy with nearly all patients exposed to prior chemotherapy and a prior anti-CD20 antibody in addition to the BTK inhibitor.

The overall response rate in this 90-patient population was 58%, which is an increase from the previous data reported. And the median duration of response in this patient population was 22 months. Taking patients who'd stopped their prior covalent BTK inhibitor for progressive disease, the response rates were also good at 50%, and the duration of response was nearly 15 months in this patient population. Pirtobrutinib in the mantle cell lymphoma patient as well as all patients in the BRUIN study continued to be very well tolerated, with very low rates of discontinuation due to drug-related toxicity at 2%.

A study called the TARMAC study was presented by the Australian group at ASH this year combining tisa-cel, a CD19 CAR T-cell therapy, with ibrutinib, [a] covalent BTK inhibitor. So the theory behind this study is that through interleukin-2-inducible T-cell kinase (ITK) inhibition, ibrutinib potentially improves the activity of the CAR T cells and potentially improves the durability. And so this is being tested as a hypothesis in this study.

The study took a patient population that was high risk at relapse or high risk because they received and were refractory to a prior covalent BTK inhibitor. So these are patients who had received prior immunochemotherapy, typically rituximab alongside anthracycline and cytarabine-based therapy. And the median prior lines of therapy was 2 in this study. A number of patients had high-risk genetic characteristics as well, including TP53 mutations, and many patients had a high Ki67, which has typically been associated with a worse outcome in mantle cell lymphoma. Half of patients have been exposed to a prior covalent BTK inhibitor and half hadn't been. So there were 2 groups that were studied in this clinical trial.

The overall response rate at 4 months was the primary endpoint, and you can see that the complete response (CR) rates were 80%, and this is also shown to be durable. Patients were able to stop the ibrutinib following minimal residual disease (MRD) negativity, and so the ibrutinib was effectively given as a time-limited treatment in this phase 2 study.

The subgroups seemed to all generally benefit from the therapy other than an intriguing finding in the patients who'd received prior bendamustine. Now, this was a small number of patients, but none of those patients responded to therapy, opening up the question about T-cell fitness in those patients that received this T-cell suppressive therapy. Encouragingly, the responses seen in patients who'd had a prior covalent BTK inhibitor and those who were naive, and there are also encouraging responses in patients who have a TP53 mutation, which have historically been associated with poor outcomes to BTK inhibitors and immunochemotherapy.

Toxicity was consistent with what we know it from CAR T-cell therapy. So most cytokine release syndrome was grade 1 or 2, with 4 patients experiencing grade 3 cytokine release syndrome. And the rates of neurotoxicity, so immune effector cell-associated neurotoxicity syndrome (ICANS), were low, with 1 patient experiencing grade 2 ICANS.

And so this is the first proof-of-concept study of the combination of a BTK inhibitor with CAR T-cell therapy. The primary endpoint was met in this study and the combination was effective. Time-limited therapy was given to most patients, so most patients were able to stop the ibrutinib, and there was encouraging efficacy, particularly in high-risk patients. And it seemed like the treatment was tolerable despite the combination study being given. So this provides a proof of concept that's worth exploring further in the future.

A phase 1/2 study of a ROR1 monoclonal antibody zilovertamab in combination with ibrutinib was studied and presented in mantle cell lymphoma, CLL, and marginal zone lymphoma. There were a number of different parts of this study. Here on this slide, there are patients who received the combination with mantle cell lymphoma and CLL. Focusing on the mantle cell lymphoma patients, you can see that patients had received 1 prior line of therapy, small number of patients that had a prior BTK inhibitor; so it was a generally BTK-naive population. Patients were generally otherwise fit, and the median age was 65 [years].

The tolerability of the combination seemed to be good, and [was] consistent with the toxicity profile that we know about from ibrutinib studies. This is a slide showing the toxicity from a combination of the different elements of this phase 1/2 study, and you can see the typical toxicities associated with ibrutinib: hypertension, fatigue, diarrhea. All of these adverse events within this study look to be consistent with ibrutinib monotherapy, suggesting that the ROR1 monoclonal antibody doesn't have significant toxicity in addition.

This is the overall response of the combination in mantle cell lymphoma and CLL. Focusing on the mantle cell lymphoma patients, there were 28 response-evaluable patients. The overall response rate was nearly 90%, and the CR rate was nearly 43%, with a median duration of response of 34 months and a median follow-up of nearly 20 months. The progression-free survival in the mantle cell lymphoma patients seems to be favorable compared with historical controls. And so this has led to the design of the ZILO-301 randomized clinical trial.

Thank you for participating in this activity. Please continue on to the next chapter where Jennifer and I will discuss the clinical impact of the data I just presented.

Segment 4

Jennifer A. Woyach, MD: Welcome back, Toby. Let's continue to discuss the clinical implications of the data that you just presented.

So first question is about pirtobrutinib. So who do you think might be the most appropriate for pirtobrutinib (pirto) in mantle cell lymphoma and where would it be best placed in the treatment pathway?

Toby A. Eyre, MD, MBChB, DipMedEd, MRCP, FRCPath: Yeah, I think that's a great question. So I think the first thing to say is we don't know exactly where this agent may be approved in the future and how many lines of therapy patients may need to have.

Undoubtedly, patients will need to be exposed to a prior covalent BTK inhibitor. And so to my mind it's in a group of patients, perhaps either pre-CAR T in terms of maybe a bridge to CAR T-cell therapy, potentially in patients who've had prior CAR T-cell therapy in mantle cell lymphoma. But of course, there are quite a lot of patients who aren't suitable for the licensed CAR T product in mantle cell lymphoma, and those patients would be very appropriate for pirtobrutinib. So those are the 3 groups I see pirtobrutinib being used in the near future.

Dr Woyach: So similar to what we discussed about CLL, do you ever see a scenario where you might use pirtobrutinib (pirto) before covalent BTK inhibitor?

Dr Eyre: So I think that's a great question, and there's an ongoing randomized clinical study which is comparing pirtobrutinib with investigator choice covalent BTK inhibitor in previously BTK-naive relapsed mantle cell lymphoma patients. It's a global, randomized trial which is ongoing at the moment. So that's the study that may influence the treatment pathway of BTK inhibitors moving forward.

The BTK resistance mechanisms in mantle cell lymphoma are substantially more complicated than CLL, and so I think that's a very open question and there's no real data to guide us as yet in mantle cell lymphoma, but it may be that noncovalent BTK inhibitors are safer and potentially more effective than covalent BTK inhibitors. And so it may be efficacy of the comparison really that drives the prescribing behavior in the future.

Dr Woyach: So you mentioned CAR T. So where do you see CAR T in mantle cell? Does it have a role further in treatment landscape?

Dr Eyre: So that's a great question. So at the moment, CAR T approval is slightly different in the US to Europe, but in Europe, the CAR T product is used in the third-line setting. I think that's most common in the US as well, but the license is broader in the United States (US).

But there are ongoing studies looking at CAR T-cell therapy in the second-line setting and potentially that has a role in patients with particularly high risk features, say TP53 mutations, very high Ki67 blastoid disease. You can see why CAR T-cell therapy, which looks to be at least from the data we have at the moment, fairly agnostic to those high-risk features, it may be that in those patients, therapy has moved further forward in into for example, the second-line setting.

Dr Woyach: And maybe like you showed us with the data you presented, maybe in combination even with a BTK inhibitor, right?

Dr Eyre: I think that's possible. I mean certainly that study provides a sort of first proof of concept of that. I think one of the difficult things with a 20-patient study is actually knowing the contribution of the addition of the ibrutinib, because that CR rate for example, is fairly consistent with what we have seen with CAR T-cell therapy in mantle cell lymphoma up until now. The response rates with the combination of ibrutinib and tisagen in that study were approximately the same as we've seen in studies of CAR T-cell therapy by themselves, so the contribution of the BTK inhibitor in that study is a little bit unclear. But we may see the addition of CAR T-cell therapy with BTK inhibitors moving forward in future pivotal studies.

Dr Woyach: So last question, can you tell us a little bit more about that ZILO-301 study and how is it testing the ROR1 monoclonal antibody?

Dr Eyre: Yeah, so the ZILO-301 study is testing the standard-of-care therapy ibrutinib with ibrutinib in addition to the monoclonal antibody, the ROR1 monoclonal antibody. The study is a randomized clinical trial, it's going to be a global study. And the design of the study is that patients receive 4 months of ibrutinib and in those patients who have either stable disease or partial remission, they're then randomized between ibrutinib given as continuous therapy, as per the approved licensed indication, vs the addition of the ROR1 antibody, so zilovertamab plus ibrutinib. And obviously the small phase 2 study that I've shown you gives the proof of concept for why there may be additional benefit of the R0R1 antibody. So that study's going to be enrolling over the coming years.

Dr Woyach: Great. Thank you so much Toby, and thank you all for participating in this activity.

This transcript has not been copyedited.