Comparing Ibrutinib, Acalabrutinib, and Zanubrutinib BTKi

EP: 1.Available BTKi and Their Mechanisms of Action

EP: 2.Ibrutinib Clinical Trials for B-Cell Lymphomas

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EP: 3.Comparing Ibrutinib, Acalabrutinib, and Zanubrutinib BTKi

EP: 4.Clinical Trials of BTKi in B-Cell Lymphomas

EP: 5.Disease Progression and Resistance to BTK Inhibitors

EP: 6.Zanubrutinib for B-Cell Lymphomas

EP: 7.ALPINE and ELEVATE-RR Trials

EP: 8.Physician Preferences on BTKi

EP: 9.Third Generation BTKi and Unmet Needs

EP: 10.Future Developments With BTKi

Mazyar Shadman, MD, MPH: There was a time when we would use ibrutinib, and then slowly we learned about the AEs [adverse events] and how to manage and play with the dose and the schedule. Then we started having access to next-generation BTK [Bruton tyrosine kinase] inhibitors. Second-generation BTK inhibitors are still irreversible binders to the BTK but basically more selective to BTK. Acalabrutinib was the first drug that became available by FDA approval for mantle cell lymphoma. The studies that looked at the efficacy used different methods, CT vs PET [positron emission tomography] scans. Looking at the CR [complete response] rates is tricky comparing studies.

What do you think of the efficacy, mainly PFS [progression-free survival] and the differences between ibrutinib, acalabrutinib, and zanubrutinib is also approved for mantle cell lymphoma in the relapsed setting? Do you see a difference in terms of efficacy itself?

Jonathon Cohen, MD, MS: That’s a good question. In my experience, I don’t necessarily consider these to necessarily be appreciably better than the other. With ibrutinib, there have been additional studies that have shown that if it’s administered earlier on during a patient’s treatment, usually as a second-line therapy, then the response duration tends to be longer. But all these have a progression-free survival somewhere in the 18-to-30-month range. You usually get between 1½ and 2½ years of remission. Some patients have been them for many years, and there are others who unfortunately progressed early. I often don’t view 1 of them as better. When I’m making a decision about an individual therapy for an individual patient, it’s more a question about drug-drug interaction concerns, scheduling, or other AEs that may lead me toward 1 vs the other.

For example, with acalabrutinib, it does appear, based on some of the recently reported data from the ELEVATE-RR study, that there may be some differences in toxicity. The ELEVATE-RR study for relapsed/refractory patients in CLL [chronic lymphocytic leukemia] was a head-to-head study between acalabrutinib and ibrutinib, and it showed that while the efficacy was comparable, there did appear to be some significant improvements in the number of AEs of interest, including atrial fibrillation and bleeding. If I have a patient for whom I’m worried about those types of complications, I might be more inclined to go with acalabrutinib. On the other hand, we know that acalabrutinib is administered twice daily. For some patients that could be challenging because it typically doesn’t go well with proton pump inhibitors, which we know a lot of our patients are taking. If I have a patient with difficult-to-control gastroesophageal reflux disease, I’m often going to think about using an alternative agent.

What about you? What are your thoughts about acalabrutinib as it compares with ibrutinib or some of the studies that have informed our management?

Mazyar Shadman, MD, MPH: We’ll talk about the studies shortly, but in CLL we have 2 randomized studies that basically targeted patients using ibrutinib who stopped the treatment because of AEs. In 2 different studies, when they went on acalabrutinib, we saw that the drug could be used, and patients were able to continue. We have indirect evidence that acalabrutinib may be something that could be used in patients who are intolerant to ibrutinib. Recently we had results from a randomized trial. One was the ELEVATE TN relapsed/refractory, which compared ibrutinib with acalabrutinib in the relapsed CLL setting. For zanubrutinib we have 2 randomized trials: 1 in Waldenström [macroglobulinemia]—the ASPEN trial was a head-to-head trial comparing ibrutinib with zanubrutinib—and then more recently the ALPINE study in CLL relapsed setting.

We’ll talk about the studies, but it’s clear that the AE profile of acalabrutinib and zanubrutinib are superior to ibrutinib. In mantle cell lymphoma, we don’t have head-to-head trials. But from the AE standpoint and from other histologies, with zanubrutinib the ASPEN and ALPINE are similar in showing that the AE profile is favorable when you compare zanubrutinib with ibrutinib.

Second-generation BTK inhibitors are better choices in terms of starting patients on a BTK inhibitor. In terms of efficacy, in mantle cell lymphoma, it’s hard to say. They’re different studies, but they seem similar in terms of the PFS [progression-free survival] rate that they’re providing. I use the same principle in looking at the AE profile. Acalabrutinib does have a few limitations, and they’re being used concurrently with a PPI [proton pump inhibitor]; the twice-a-day dosing may be important for some patients. Zanubrutinib doesn’t have those 2 limitations. The dosing could be twice a day or once a day. But they’re both great drugs. There’s no way to comment about the 2.

I wanted to ask you a question that I get often from some colleagues. In mantle cell lymphoma we have the question of adding a CD20 antibody to BTK inhibitor. In CLL we have clear evidence that rituximab doesn’t add anything from the efficacy standpoint to ibrutinib. In the ALLIANCE study, the ibrutinib and ibrutinib-rituximab were basically identical. In acalabrutinib and obinutuzumab, the story is different. We’ll talk about the ELEVATE TN study. In mantle cell [lymphoma], when you look at the ibrutinib-plus-rituximab efficacy, it looks better than single-agent ibrutinib. Do you believe ibrutinib should be given in combination with rituximab in mantle cell lymphoma? If so, how do you use that information when you use a second-generation BTK inhibitor? Do you also give acalabrutinib or zanubrutinib with a CD20 antibody?

Jonathon Cohen, MD, MS: Yes. I’ll make this a little easier. I typically haven’t been combining a BTK inhibitor with CD20 antibody. You’re right: there might be some improvements in outcomes. It’s hard to say. We have the SYMPATICO trial, which did incorporate a doublet arm of obinutuzumab and ibrutinib. At least some of the initial data look quite good. Even though it’s not a part of my standard practice here in the late summer of 2021, that doesn’t mean that that may not change moving forward. Some of our best data with the incorporation of BTK inhibitors in the frontline setting, not approved, are from the Window trials from [The University of Texas] MD Anderson [Cancer Center], which have incorporated rituximab and ibrutinib have had a very high overall response rate and CR [complete response] rate in patients with untreated mantle cell lymphoma.

As we can start to think about using ibrutinib earlier in the treatment course, that incorporation of CD20 antibodies in that setting will likely make a lot of sense. For patients with relapsed disease, it’s not clear to me that adding in the CD20 is critical in a patient who’s already received rituximab-based therapy, especially in the current era, when so many patients are receiving rituximab maintenance as part of their consolidation or postinduction therapy. That is a landscape that could certainly change. As opposed to CLL, we know that BTK inhibitors, while highly effective in mantle cell lymphoma, don’t seem to have that same duration of response. Whether combining with CD20 or some of the other novel agents out there is what we ultimately need to do, there’s room for improvement where we are with the single-agent BTK inhibitors.

This transcript has been edited for clarity.