Clinical Trials in Zanubrutinib for Chronic Lymphocytic Leukemia


Dr Kirollos Hanna details clinical trial data on the use of zanubrutinib in treating chronic lymphocytic leukemia.

Kirollos Hanna, PharmD, BCPS, BCOP: Another important trial that I do think we have to mention that was presented at ASH [American Society of Hematology Annual Meeting 2021] is the SEQUOIA trial, which also looked at the zanubrutinib [Brukinsa] in the CLL [chronic lymphocytic leukemia] patient population that were treatment naive. This was a phase 3 trial with randomized patients to either receive zanubrutinib at 160 milligram BID [twice a day] or to receive bendamustine [Treanda]/rituximab [Rituxan]. So a combination chemoimmunotherapy vs BTK [Bruton tyrosine kinase]. Now, a notable thing that we have to highlight about the SEQUOIA trial is that the patients included did not have the deletion 17p mutation. That is something that is important for us to understand. Although some of the additional data that we have from zanubrutinib does show that it is effective in the deletion 17p patient population as well. What we noticed in this trial or what was reported out of the SEQUOIA trial is that the progression-free survival by independent review was significantly prolonged with zanubrutinib vs chemoimmunotherapy. Again, nothing new there. The hazard ratio there was 0.42, and ultimately the estimated 24 months for zanubrutinib was about 85.5% in the patients that receive BTK. And in the BR [bendamustine, rituximab] arm, it was about 70%. So that was notable. And then again, similar to what we would expect, adverse events revolving from our BTK inhibitors aligned with what we are already familiar with vs the chemoimmunotherapy. We did see some cardiac arrhythmias, and we did see some hypertension. What was more notable and more profound were neutropenia, some infectious complications, and aches and pains, whereas, with the chemoimmunotherapy, it was predominantly the neutropenias. Dr Perissinotti, you had mentioned, outside of this data, when we're selecting therapy, what do we do in terms of our BTK inhibitors? I mentioned there are adverse events when we talk about BTK inhibitors as a whole that are of interest, but there are certainly differences there. And, a lot of times, these adverse events revolve around bleeding or hemorrhage. Maybe if you’re talking about acalabrutinib [Calquence], it may revolve around headaches. If you’re talking about select therapies, then maybe around the neutropenias or infectious complications. And in certain cases, there’s going to be cardiac arrhythmias, your A-fib [atrial fibrillation], and your A [atrial]-flutters, and we do see some differences there. And lastly, it’s going to be important to also highlight that we can see some differences in hypertension. What we also saw [at] ASH, in terms of head-to-head comparison; [John F.] Seymour [Peter MacCallum Caner Centre, Victoria Australia] and colleagues actually presented, they had an abstract at ASH that looked at head-to-head comparisons of acalabrutinib vs ibrutinib [Imbruvica]. Ultimately, in this trial, it was patients with previously treated CLL, and these patients were randomized to the standard doses of either acalabrutinib, so 100 BID, or ibrutinib at 420 milligrams, once daily. What we did notice in this clinical trial or this comparator trial is that the incidences of any great cardiac arrhythmia, so A-fib, A-flutter, hypertension, and the bleeding incidences were statistically higher with ibrutinib.When we talk about that, ventricular arrhythmias were reported in 3 ibrutinib patients and 0 patients in the acala [acalacrutinib] arm. Additional BTK AEs [adverse events] that occurred, diarrhea, arthralgias, contusions, UTIs [urinary tract infections], aches and pains were also statistically higher in ibrutinib at about 1.5 to 4.1 fold higher. Exposure adjusted incidences rates favor acalabrutinib in terms of the safety incidences vs the ibrutinib. So pretty profound differences there in some of these drugs. When we actually look at some of the data that we’ve been accustomed to, there has been real-world data published out of Ohio State that has informed us that, based on real-world experience, some of those AEs do lead to discontinuations. Dr Perissinotti, before I turn it over to you, the last thing I think that’s important for us to also highlight is we talked about the comparator between acala [acalacrutinib] and ibrutinib, but now the ALPINE study. The ALPINE study compared zanubrutinib vs ibrutinib. This study is also why I had mentioned that we do have enough data to show that zanubrutinib is also effective in the deletion 17p patient population vs what I had mentioned earlier. But when we talk about the ALPINE trial, this was a global randomized phase 3 trial that compared zanubrutinib vs ibrutinib in the second-line setting or at least in the relapsed/refractory patient population. And what we saw in this trial, not only did we see differences in the safety, but there were some efficacy signals that were also observed in this clinical trial. At a median follow-up of about 15 months, the response rates were significantly higher with zanubrutinib vs ibrutinib; that was 78% vs about 62.5%, and that was deemed statistically significant. This was also higher in patients with high-risk cytogenetics, such as deletion 11q or even deletion 17p. And with the 12-month progression-free survival there was also about 95% in zanubrutinib vs about 84% in the ibrutinib treated patient population. In terms of AEs, atrial fibrillation, which was 1 of the adverse events that was focused on as well as hypertension, and we did see fewer incidences in the patients that were treated with zanubrutinib over ibrutinib.

Transcript edited for clarity.

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