Clinical Considerations for BTK Inhibitor Treatment Selection

EP: 1.Mechanism and Frontline Use of BTK Inhibitors in CLL

EP: 2.Covalent BTK Inhibitors in Relapsed/Refractory CLL

EP: 3.Comparing BTK Inhibitors: Key Findings from Head-to-Head Trials

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EP: 4.Clinical Considerations for BTK Inhibitor Treatment Selection

EP: 5.Molecular Mechanisms of Resistance to Acalabrutinib in CLL

EP: 6.Treatment Options for Patients with CLL Progressing on Covalent BTK Inhibitors

Dr. Brian Hill: So then I'll ask you, Dr. Ghia, so how do you choose between a BTK inhibitor in frontline or in the relapse refractory setting?

Dr. Paul Ghia: Well, that's a difficult choice, but we are happy to have difficult choices because it means that indeed we have plenty of molecules that are all effective. Definitely the, the landscape we are facing now and our patients are facing much better than in the past with chemo immunotherapy. So we know that with BTK inhibitors, now we can control also patient with P 53 aberrations. So this is something reassuring and all patients, virtually all patients respond. So there is no difference, for example, anymore between patient with unmutated immunoglobin genes and mutated immunoglobin genes. So we are starting really from solid ground. We can almost promise a response to all our patients. Having said that, we can choose picking on the details, and definitely the second generation molecules like acalabrutinib zanubrutinib show to be better tolerated than ibrutinib. It seems that acalabrutinib is better tolerated under different aspects. So, as I mentioned earlier, atrial fibrillation, general cardiovascular toxicity, so hypertension atrial fibrillation, but also as we said, arthralgia myalgia seems to be of less relevance with acalabrutinib. It is true that acalabrutinib, for example, can give a headache, but this is typically short lasting happening in the first two, three weeks. So it is really something that should not really change our mind. The data on efficacy or the better efficacy with zanubrutinib compared to ibrutinib, of course, are interesting and therefore worth exploring. It is true that the design of the study is different. So we cannot really understand how, for example, zanubrutinib might compare with acalabrutinib, we might talk about this later on. The ibrutinib seemed in the study to perform worse than typically in other studies and also probably in our real world evidence. So it's difficult to evaluate that aspect. But also zanubrutinib gives less atrial fibrillation. So it's better tolerated. So it is probably ibrutinib will somehow will become a second choice as indeed NCCN guidelines are already stated and put on paper.

Dr. Brian Hill: That's right. And I think it is important to notice that the follow up of ELEVATE-RR is longer because the study was launched sooner and report we have a little longer follow up compared to Alpine.

Dr. Paul Ghia: Yes. So we spoke about hypertension, we spoke about cardiovascular toxicity, how these factors are taken into your decision process.

Dr. Brian Hill: Yes. So for a patient who is starting on or needs treatment for either relapsed refractory or frontline therapy and the choices made for a BTK inhibitor, I think the point is well taken that we know that both acalabrutinib and zanubrutinib are superior in terms of safety relative to ibrutinib. But we don't have head-to-head trial of acalabrutinib versus zanubrutinib. So it is difficult to compare across trials. We do see maybe a little more hypertension with zanubrutinib. We see more headache with acalabrutinib, so they both seem very well tolerated, and I think that's been borne out in real world experiences as well. And so it's difficult to say that one is clearly better than the other at this point.

Dr. Paul Ghia: And actually what we can also say and suggest is that probably before starting BTK inhibitors, we should really do a very thorough cardiovascular workup of our patient because it's always good to know how your patient is feeling, how they are doing, even when they start venetoclax or obinutuzumab, you want to know exactly how the cardiac performance of your patient is if they had already history of hypertension. So that's probably one of the major advices, one of the major lessons that we learned when using the BTK inhibitors. But you mentioned a couple of times about real world data, so maybe you want to comment how this data fit into the picture. In particular, you might refer to a couple of studies that have been shown at ASH last year, or both of them actually. Yes.

Dr. Brian Hill: Yes. So at the 2022 ASH meeting, we saw a couple large data sets of so-called real world experiences. These were drawn from large databases that examined the safety and efficacy and discontinuation rates of ibrutinib and acalabrutinib in the real world. And consistent with the prospective trials, what we saw is significantly less discontinuation of acalabrutinib versus ibrutinib in broad prescribing patterns well beyond what the typical patient population for a clinical trial may be. So I think that those real world experiences are very helpful in validating what we've seen in the prospective studies because again, the patient population is not always the same.