Hello, I’m Marek Trněný and I’m based in Prague Charles University General Hospital. And it has been a great pleasure to share this session and to discuss very important and interesting issue of BTK inhibitors.

Yes, I think the challenge and I kind of kicked off the session is how do you choose when you have so many BTK inhibitors available? And so I kind of kicked off. What is our current experience with ibrutinib and when you might consider it, particularly in combination strategies? I think one of the challenges are the obvious challenge with Ibrutinib is it’s It’s a drug that we’ve had longer, so we have more mature data. But it’s also perceived to be less well tolerated and maybe even less effective in some of the studies. And so what I set out to do is kind of cover my experience with Ibrutinib, where I see still a role for ibrutinib been kind of where we may move forward currently, where we’re exploring ibrutinib. Still, in prospective studies and combination strategies, and particularly in lymphoma subtypes, we have a pretty strong preclinical rationale to combine it with agents that are going to further augment the micro environment. And so I covered Jason Westin’s recently published Smart Start study, looking at a lead in of a non-chemotherapy option with rituximab, lenalidomide and ibrutinib. And after two cycles, he had a response assessment. He also had circulating tumor DNA to really get a sense of What is a targeted non chemo approach? How does it performed in previously untreated large cell lymphoma? There’s a safety net and then adding in the chemotherapy, so patient still got six cycles of either CHOP or, uh, EPOCH. But I do think it’s intriguing because he saw about a 40% response rate in upfront. He also demonstrated that are Hans algorithm is not 100% concordance. So we did have GCBS in there when we looked at molecular profiling. But interestingly saw responses, even with the targeted therapy just among the GCB patients. So that’s intriguing sort of signal finding. It’s not a practice-changing study, but at least an opportunity to try and explore a targeted option with ibrutinib frontline large cell lymphoma. What were your thoughts about the Smart Start study?

Yeah, I think that this is a really very important proof of the concept and, uh, when I talked about acalabrutinib, I just presented the current running study, which is combining not only the BTK inhibitor. So in this case, it’s not ibrutinib. It’s acalabrutinib. It together with the rituximab and what we call L-MIND combination actually combination based on L-MIND. It means, uh, anti CD19, uh, engineered antibody tafasitamab, um, plus lenalidomide. So it means there are the four combinations, and I think that based on the data we have seen, and I think that it’s very, very interesting that one patient refused to get to get chemo in the smart study and he’s in the remission for three years. So it’s, uh, it’s really encouraging. But what I think it’s very important for the new smart Stop study is that it’s not only combining the new drugs and more drugs, but it has. It’s based on the response adapted approach, so it means not only general hematology Lugano criteria response, but based on the ctDNA measured MRD. So it this is very important. The study is not big, but I think that it really could help us better understanding how those drug works and maybe why fail in some in some patients, But it needs to really huge translational approach.

And I think you know, if we’re going to move beyond, particularly anthracycline based therapy in frontline large lymphoma. We have three decades of understanding what the cure rates are. We better have a strong rationale for why you might choose a targeted therapy. And so it’s step one, as you mentioned, there, are following studies with more targeted BTK inhibitors, such as acalabrutinib we also covered the SHINE study, which I think is a little bit controversial. But it’s an older study. It took a long time to read out, but it looked at bendamustine rituximab followed by rituximab maintenance plus minus ibrutinib in untreated mantle cell lymphoma. It was a large international Phase III study. It’s a positive trial and its primary endpoint, including ibrutinib in combination with BR led to an improvement in progression-free survival. No difference in overall survival. And actually the safety profile was less favorable in the ibrutinib containing arm. So I think there’s some room there for discussion about. Is this actually practice changing, or is it an interesting study that was positive. My general census. There might be better strategies in terms of sequencing as opposed to combining. Um, how do you interpret the SHINE study?

Yeah, I agree. So the study is positive by definition, so it has improved the progression free survival. But I think that the BR itself is very effective regimen. And if it is followed by the rituximab maintenance, I think that especially in the elderly patients, the rituximab maintenance plays role. So it has been shown by European Mantle Cell Lymphoma study published some time ago. It really changed and improved overall survival only rituximab maintenance. So I think that it’s still some room for improvement. Maybe it’s because of the combination with the BR. So I just could invite everybody just to see the abstract and the presentation on upcoming ASH. This is the other ibrutinib testing mantle cell study. It’s a European Mantle Cell Lymphoma network study TRIANGLE, which compares three arms just under the arm. Because for the young patient is the our chemo R-CHOP/DHAP, followed by the stem cell transplant, and then based on the regulation ibrutinib maintenance. This is the standard. Um, and there are two experimental arms; one at Ibrutinib, including the maintenance. But it’s stem cell transplant is part of the study of the treatment, and the third arm is ibrutinib. But we try to skip high dose treatment, and after the stem cell transplant, I can definitely share the data. But I really highly encourage everybody to to look for the data at upcoming ASH.

I think that’d be a really exciting study to see. So I finished up my session with covering sort of ways we might manipulate T cells with given sort of the off target effect, at least what we kind of understand about the impact on T cells to BTK inhibition. But either using it in combination with the checkpoint inhibitor and Richter transformation, or, uh, to try and manipulate T cell fitness for patients who are intended for autologous car T cell therapy. So giving it even before before you collect the cells through the bridging and through the cellular therapy acute toxicity window again, just some insight in terms of where ibrutinib might still have a role. But then you kicked us off with acalabrutinib and shared some interesting data where that might be a more attractive BTK inhibitor.

I think that the ibrutinib is more selective BTK inhibitor so less of target. So maybe it could help to the better safety profile. But basically speaking, we have one Phase II, we have one head-to-head study, which shows in the CLL small lymphocytic lymphoma, it has shown no efficacy difference. So the median progression-free survival in both arms 38.4, hazard ratio 1.0. So it means totally, totally identical, identical data. But the safety profile is better. Um, what I think what is very important is to discuss how to use these more specific, more specific, uh, more selective targeted BTK inhibitors. You we have heard the Alessandra Tedeschi talk on zanubrutinib so and it’s interesting that when uh, he recapitulate when she recapitulated, the studies had to have zanubrutinib versus ibrutinib. So it’s not only benefit in terms of the safety profile, but there is a benefit in terms of the efficacy which favors zanubrutinib So this is this is important part as well.

That was really intriguing. I said that we’ve always sort of assumed that the more selective BTK inhibitors have a safety advantage, but showing that it could also have an efficacy advantage. I think that’s gonna be intriguing to see more mature studies. The other thing that she talked about, which I also find intriguing, was the ROSEWOOD trial, which is zanubrutinib in combination with, obinutuzumab versus obinutuzumab in relapsed follicular because I sort of was of the impression that wasn’t really a role for BTKi, at least not ibrutinib in follicular lymphoma. But this kind of opens the door again that there might be some activity. What were your thoughts about that?

I think that it’s for some population, definitely, it could work, so I completely to be to be honest, I do not know if this study is going to lead to the approval for the follicular lymphoma, but I think that for some patients, it really could be advantage if they can have this combination. Uh, obinutuzumab itself is not approved for the relapsed refractory patients except the, uh obinutuzumab bendamustine for rituximab-refractory patients. But what I do during the study what I really find very interesting is the pirtobrutinib study because this is not irreversible. This is the reversible BTK inhibitor, and it has been used at least this part of the study on the relatively large cohort of the patients. More than 200 patients, which really shown that, and all patients were pretreating with the BTK. So it’s and it really shows very promising data. So what do you think about it?

I think it’s really intriguing for two reasons, because Anthony Mato kind of focused on the patients that had failed BTK inhibitor were actively progressing and then highlighted some of those that had mutations in the BTK binding site or downstream the PLC Gamma, though that was only two patients and frequent and then a small portion patients that failed because they couldn’t tolerate BTK inhibitor and kind of made an argument for this agent having activity in both scenarios. So then the question that I wonder is Okay, now, how do we sequence these therapies? Do you save it for those patients who failed ibrutinib or acalabrutinib, or do you use it up front and then with the idea that you’re not going to introduce those mutations.

Yeah, definitely. So we do not know if it works in the front line in the same level, so it means we have to. Finally, we have to have the have to have a comparison, but I think that it’s it’s really full time being. I think, that it’s a very good option for those patients who fail BTK inhibitors because the safety profile is, uh is quite favorable and in the mutation on the BTK. So it means that the patients without and with mutation, they have no, uh no difference. So I think that it’s it’s it’s really important. So if we have discussed the CNS lymphoma as well, so it means so There is some data on the BTK inhibitors. There is some data on checkpoint inhibitors. So how you how you explore those agents in the primary CNS lymphoma Not in primary CNS lymphoma, in relapsed primary CNS lymphomas.

So most of our patients who fail the high dose methotrexate-based approach we’re looking for a BTK inhibitor combination strategy, I’d say as a single agent is probably modest activity. But it is an agent that will potentially have activity in, uh CNS, so that’s attractive. Jason Westin actually has a study with ibrutinib in combination with nivolumab for those patients. Small number of patients It’s early, but there’s a signal there, so I do think they there will be combinations moving forward that are attractive.

And what about the combination with other approaches, like the CAR T cell or some bispecific antibodies? So what do you think? So is there is there room for these combinations? BTK inhibitors and these, Let’s say, T cell engaging therapies.

I think one of the features about ibrutinib that makes it kind of attractive for those combination strategies is the impact on the T cell subtypes or phenotype. And so, yes, I think those strategies are potentially promising. I think the challenge will be is that What are the resource utilization issues going to be because you’re talking about super expensive therapies with car T and by specifics. And now we’re tacking on a targeted agent that’s going to have probably continuous therapy, but I think that’s intriguing. I think it also raises questions about the other BTK inhibitors that are by definition, more selective. Do they have similar impact on T cells and macrophages. And, uh, well, they also be sort of interchangeable in terms of those combinations that those questions I don’t know the answer to.

And there is the other issue. So we came to So based on the Smart Start study, Smart Stop study and maybe some other trials. So the question is so the immunochemotherapy backbone is needed will be needed for all patients for just the selected patients. And could we skip in some course? So what’s your sort of, for diffuse large B cell lymphoma patients in the future? So what are your sites for the future?

I think generally how we’ve pursued drug development is you take a therapy that you have confidence is going to work, and then you build on it. You add another drug on, and there’s been a lot of failed studies in that approach, and so I think we probably need to move away from that and maybe do either a lead in or maybe even just a targeted approach. If you can feel confident in patients where that’s going to be better, um, or could replace the chemoimmunotherapy. I think the challenge, if you do build onto that backbone, you’re gonna have additive toxicity. Um and then the challenge is, if you’re not gonna be able to deliver the therapy that you think you’re having the most confidence is going to be the curative approach. Then there’s going to be a little appetite for that. So I think if you have a targeted approach that has synergy with your chemotherapy or your backbone of choice, that makes sense. But just to add on, I think we might just have additive toxicity and not a lot in terms of efficacy. And we can learn from the POLARIX study where you might feel back something and add something in that might be an attractive strategy. But I’d really like to see more studies done where we get a better understanding of the underlying biology, target it and shorten therapy as opposed to expanding on to our backbones.

Yeah, I completely agree so and what I think is very important to study those patients on the mutation profiling, etcetera because just to discriminate GCB and non-GCB based on the immunohistochemistry at the end, you still end with a very heterogeneous group of patients, so I think that for the targeted therapy, we really need to to have a very good understanding who are treating with those therapy and understand what is going to happen if this therapy fails. So it means to re biopsy. So it is challenging for the patient. But it is challenging for the, uh, for the study teams as well. So But I think that based on this section of what we have seen, so it’s it’s the BTK inhibitors is not only for the CLL and the mantle cell, but definitely could play a role in Waldenstrom’s. And so we haven’t mentioned the Waldenstrom, which is very important, very important field for the patients who are failing the first line immunochemotherapy.

My takeaway is we’ve got several options. Distinguishing between them is probably going to be mostly based off of safety profile. But maybe some signs in terms of efficacy and again, whether or not we can avoid resistance down the line. I think that’s only good news for patients.

Yeah, completely agree. So it’s a great session. Thank you. Thank you. I appreciate it. Thank you.