Lipsky Discusses Second-Generation BTK Inhibitors in Relapsed/Refractory CLL

Andrew H. Lipsky, MD (MODERATOR)

Assistant Professor of Medicine

Columbia University Medical Center

New York, NY

EVENT REGION Maryland, Virginia, West Virginia

PARTICIPANT LIST: Elliot M. Epner, MD | Arun Bhandari, MD | David Weng, MD, PhD | Ikechukwu I. Akunyili, MD | George Kannarkat, MD, PhD | Donald R. Fleming, MD | Qamar Zaman, MD | Qiwei Gai, MD, PhD | Henry B. Fox, MD | Mohammad Ahsan Alamgir, MD

Epner: Because he [experienced progression] fairly rapidly,…I would move on to something else.

Bhandari: I agree; we have other good options. It [should be] a move to a different mechanism of action.

Weng: I would consider it depending on the duration of benefit. We re-treat with rituximab [Rituxan], so I don’t think it’s different in that context. If you have patients with indolent CLL, sometimes you’ll treat it with 4 treatments with rituximab and depending on the duration of the response, you might re-treat them with rituximab…. Re-treating with the venetoclax/ obinutuzumab regimen…is reasonable.

Akunyili: If I’m going to re-treat, I’ll probably be considering venetoclax alone, and I will no longer be thinking of time-limited therapy. I’ll be thinking of continuous therapy.

Lipsky: You know the treatment duration for venetoclax in the frontline setting. We saw the data from [the CLL14] study [NCT02242942]…and with 6 years of follow-up, the median progression-free survival for a patient getting venetoclax/ obinutuzumab is approximately 6 years from starting therapy.¹ That’s a year of therapy and 5 years off therapy.

If a patient gets 2 years of treatment-free interval on venetoclax/obinutuzumab, then it’s often reasonable to do re-treatment because the patient may respond there, although the number of patients that we see in practice where that ends up being an option ends up being somewhat lower because most patients actually do better than that. Most patients get 5 years off therapy. In the case of retreatment…or maybe just continuous venetoclax, sometimes that’s done, [but] the expert recommendation for this is consider retreatment as a possible option. Depending upon whether patients have high-risk mutations, some physicians would say to leave them on continuously. I think these are all good options.

Saying, “I don’t like the duration of that response. I think I can do better with a BTK [Bruton tyrosine kinase] inhibitor,” is also totally justified. We know that the responses to BTK inhibitors in the relapsed/refractory setting are also excellent.

DISCUSSION QUESTIONS

• If you choose to use a BTK inhibitor in the second line: How do you characterize the efficacy of acalabrutinib (Calquence) vs ibrutinib (Imbruvica)?
• How do you characterize the efficacy of zanubrutinib (Brukinsa) vs ibrutinib?

Lipsky: We have some comparisons between the second-generation BTK inhibitors, acalabrutinib vs ibrutinib and zanubrutinib vs ibrutinib. For acalabrutinib vs ibrutinib, what do you think about the efficacy? Is [your preference] coming from a particular clinical trial? Is that coming from…just [prescribing] it over the years?

Kannarkat: I still have some patients on ibrutinib who have never switched to any other line of treatment. Trying to compare my patients on ibrutinib with my patients whom I have on zanubrutinib or acalabrutinib, acalabrutinib and zanubrutinib have fewer cardiac issues, less atrial fibrillation, and in general are tolerated more easily. I have some patients who seem to have more musculoskeletal issues with ibrutinib, but they still seem to be sticking it out with ibrutinib and doing relatively well. In my practice, I just haven’t had that many ibrutinib failures, but when I have new patients, I’m not going with ibrutinib much.

Lipsky: It sounds like you have some good experience managing some of those toxicities. Preventing patients from [discontinuing] the drug is sometimes an art, knowing when to do dose holds and dose reductions. But you are certainly right. We have long-term data for ibrutinib. We saw a 10-year follow-up from Adrian Wiestner, MD’s NIH [National Institutes of Health] study.²

Fleming: I’ll tend to use anything other than ibrutinib because of the adverse event [AE] profile, but all BTK inhibitors are likely to interact with some of the medications this patient’s on. You have to be concerned about some of the myelosuppression that could occur with amlodipine in particular.

I have used ibrutinib in situations where some of my older patients refuse to swallow pills…because it’s the only one that comes in a solution, because it’s indicated for pediatric graft-vs-host disease. For the most part, I think the later-generation BTK inhibitors are much better tolerated, but they all will have some interactions with the medications this patient’s on.

Lipsky: That’s a good point. The other thing I would highlight is this is a patient on dual antiplatelet therapy. We all know about the hemorrhagic complications of BTK inhibitors. You might want to call the cardiologist and say, “How recently was that stenting? Does this patient really need dual antiplatelet therapy?” …Dual antiplatelet therapy is not an absolute contraindication, but making sure that…wasn’t something that could have been taken off a long time ago is something I would do in this case.

Bhandari: Ibrutinib is now 1 of those 30 drugs where it’s a capped cost [for patients with Medicare].

Lipsky: Yes…. I personally have not [prescribed] ibrutinib since that happened, so I have not utilized that.

Fleming: I would probably choose acalabrutinib. It’s been my go-to because it came in before zanubrutinib as an improvement over ibrutinib. Patients do claim they have headaches pretty often with it, and I’ve always just told them, as I’ve been told, some caffeinated beverages will help. Most of them tolerate it quite well. I tend to have an older patient population that is more into sustained treatment than trying to go aggressive up front for a finite treatment period.

Lipsky: You are right in the sense that…the ELEVATE-RR trial [NCT02477696] has been on the scene for a few more years than the zanubrutinib relapsed/refractory study [ALPINE; NCT03734016]. There is some first-mover advantage there. It is true…that headache [associated with] acalabrutinib is unique to acalabrutinib and is not seen with zanubrutinib or anything else.

Zaman: I think it’s important to have something that has a long duration of response. Length of follow-up and response rate are also important. If I have to choose [a second option], that would be safety profile.

Lipsky: Absolutely. I think that CLL is not the same kind of disease as diffuse large B-cell lymphoma, and progression-free survival [PFS] is particularly important.

Fleming: I chose safety profile first because all these drugs are very effective against CLL, but we’ve already knocked [ibrutinib] out of use practically because of safety issues alone. That’s why I picked it.

Akunyili: Do we consider ibrutinib to be unsafe? I think we’ve been a bit unfair to a very good drug that has been there for a very long time. If…that was the drug I had for CLL, I’d be very excited. It’s not necessarily an unsafe drug, it’s just that we have other drugs. One of the things that’s not mentioned is finances. Some people want to be on once-daily medication. There is nuance.

Lipsky: I think those are important points.… How much the magnitude of some of these differences in terms of safety effects matters in the clinician’s hands may be different than in other disease settings. These are all the same mechanism of action. I do not think that ibrutinib is an unsafe drug. We had this drug for many years. I do counsel patients who are on ibrutinib about the cardiovascular risk, and the very rare risk of sudden cardiac death and arrhythmias that are associated with that drug. But your point is very well taken that ibrutinib is a major advance and a very efficacious drug.

CASE UPDATE

Due to progression after a BCL2 inhibitor, a decision was made to start treatment with a BTK inhibitor.

DISCUSSION QUESTIONS

• Consider the data for ALPINE and ELEVATE-RR: How do you interpret the efficacy and safety outcomes?
• Do you think PFS is a relevant end point in a disease like CLL?
• Can these data be cross-applied to first-line therapy?

Gai: [The study data] clarified a lot of things for me. From the ALPINE trial, as I can interpret, it looks like zanubrutinib is safe and more efficient [than ibrutinib] in terms of PFS [From the Data³]. If you look at the ELEVATE-RR trial [data], the efficacy is similar, but acalabrutinib appeared to be safer [than ibrutinib] in some of the AE profiles.⁴ That’s my take from those 2 trials.

Epner: Zanubrutinib looks better, but they obviously need to be compared against each other. But for my take, why use acalabrutinib when you can use zanubrutinib?

Lipsky: [They were investigated] with different patient populations. I think it would be great if these drugs were compared head-to-head. Unfortunately, I don’t think anyone is going to fund that study, and [there have been] efforts to try to correct for the fact that these studies had different patient populations. The closest we might get is some adjusted analysis to try to put these 2 studies together and compare [their data] in a safe way.^5,6

It seems clear that these are both safer than ibrutinib, but putting acalabrutinib vs zanubrutinib is a little [less clear]. What about the PFS end point? Do we think that’s a relevant end point in a disease like CLL?

Fox: I think it’s relevant. Nobody thinks it’s a curable disease, so you’re not looking for some proof of cure. I think there’s meaningful PFS with these drugs in this disease.… We don’t have the ideal data. We don’t have comparable trials. We certainly don’t have a trial comparing one of the newer BTKs against another one of the newer BTKs. We’re…using data that are less than complete and less than perfect, and we make our decisions with that.

Weng: Do you know what the minimal residual disease [MRD] data are for acalabrutinib or zanubrutinib?

Lipsky: Here, the relevance of whether you choose to use an anti-CD20 combination partner matters a lot. For [a single-agent] BTK inhibitor—ibrutinib, acalabrutinib, or zanubrutinib—there are low [rates] of MRD negativity. I’m talking about a range of 10% or under. But the relevant differences there when you’re comparing continuous therapy with fixed-duration therapy end up coming out when you try to use MRD as a surrogate end point for PFS. When I give venetoclax/obinutuzumab and I check [the patient’s] MRD status, that tells me how likely you’re long to go on venetoclax/obinutuzumab [after] reaching MRD.

We saw the 10-year follow-up data [showing that MRD] on a BTK inhibitor doesn’t matter.¹ It’s only a small number of patients that get there. We did see some data that there are patients that get there even years later, but your PFS is going to be fine anyway. In general, the way I think about it in CLL is if you choose a BTK inhibitor, don’t check MRD, and even if you use time-limited therapy, it’s not exactly clear what we’re going to do based on MRD. Some of these newer trials are MRD stratified and randomized, et cetera, but in general, I don’t care about MRD status with BTK inhibitors because [although] there is some apoptosis triggered by these drugs, patients don’t achieve MRD negativity, and in terms of the cash value of how long they’re going to be on a BTK inhibitor, it doesn’t matter so much.

Alamgir: We have some data that ibrutinib is superior to FCR [fludarabine, cyclophosphamide, and rituximab], which used to be one of our first-line treatments. But the other thing that I find interesting is…the ALPINE trial was after 1 line of treatment. It would be interesting to go into detail on what was the first line. Was it bendamustine plus rituximab? Was it FCR? Or was it venetoclax? Then we would know what happened in the ELEVATE-RR trial…. If everybody is already exhausted and [experienced progression] on venetoclax and bendamustine plus rituximab, then maybe the acalabrutinib data [aren’t different]. But if it’s only second-line treatment after…weekly rituximab and something else, then the second-line data favor zanubrutinib by quite a bit. But even if you don’t do a cross-trial comparison, we compared acalabrutinib with ibrutinib and we compared ibrutinib with zanubrutinib, where the ibrutinib is constant, and it seems like zanubrutinib did do better.

Lipsky: …What you’d really want is granular data for these trials, and you’d be able to look at them and [ask], “The patients who got similar first-line therapy, how did they do?” Unfortunately, those data are not available here.

REFERENCES:

1. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the phase 3 CLL14 study. Blood. Published online July 10, 2024. doi:10.1182/blood.2024024631

2. Itsara A, Sun C, Bryer E, et al. Long-term outcomes in chronic lymphocytic leukemia treated with ibrutinib: 10-year follow-up of a phase 2 study. Blood. 2023;142(suppl 1):201. doi:10.1182/blood-2023-182397

3. Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Blood. 2023;142(suppl 1):202. doi:10.1182/blood-2023-174289

4. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

5. Kittai AS, Skarbnik A, Miranda M, et al. A matching-adjusted indirect comparison of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia. Am J Hematol. 2023;98(12):E387-E390. doi:10.1002/ajh.27110

6. Shadman M, Brown JR, Williams R, et al. Efficacy of zanubrutinib versus acalabrutinib in the treatment of relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC). Presented at: 28th International Congress on Hematologic Malignancies; February 29-March 3, 2024; Miami, FL.