ASH 2024: Expert Highlights Zanubrutinib's Sustained Efficacy, Favorable Safety Profile in CLL

In an Q&A discussion with Pharmacy Times®, Mazyar Shadman, MD, MPH, associate professor of the clinical research division at Fred Hutchinson Cancer Center in Seattle, Washington, discusses highlights and important data points from the abstract of the long-term follow-up of the SEQUOIA study analyzing zanubrutinib (Brukinsa; BeiGene) in patients with chronic lymphocytic leukemia (CLL). Shadman elaborates on the sustained efficacy and favorable safety profile of zanubrutinib, with deepening responses over time and no new safety signals observed.

Mazyar Shadman, MD, MPH

Shadman is presenting this abstract on Sunday, December 8 at the 66th American Society of Hematology Annual Meeting and Exposition.

Pharmacy Times: What are the key implications of the long-term data from the SEQUOIA study for the treatment of chronic lymphocytic leukemia (CLL)?

Mazyar Shadman, MD, MPH: I’m happy to talk about it. This is an important study. SEQUOIA was the study that led to the approval of zanubrutinib in the first-line setting, and here at the Fred Hutchinson Cancer Center, we have been heavily involved in the development of zanubrutinib between the SEQUOIA trial, ALPINE, and Study 215. With SEQUOIA, as I said, this is the study that led to the approval, so long-term follow-up is always critical to understand the continued efficacy. Also, sometimes there is a new safety signal that you want to look at in the long-term follow-up to learn about. It’s mainly to understand how well the drug is working with the longer follow-up, and whether there is a new safety signal. The drug continues to work really well, with continued efficacy, and I would say a highlight of this follow-up is the fact that we are seeing deepening of responses with longer follow up with a BTKi as monotherapy. So that's great. And second is the fact that we are not seeing any new signal in terms of safety concerns, and if anything, we are seeing that some of the adverse events of interest seem pretty similar between the 2 arms. I think that's an important message to give to our CLL community.

Pharmacy Times: How does the safety profile of zanubrutinib compare to traditional therapies like bendamustine-rituximab (B-R)?

Shadman: The 2 treatments are fundamentally different, right? The control arm here as bendamustine-rituximab (B-R), 6 cycles of chemotherapy, you deal with the standard chemotherapy side effects and risk of infections and cytopenia. With zanubrutinib, you're looking at a drug that patients are taking for, in this follow up, a median of 5 years, right? It’s important for studies like these to adjust the exposure time; you want to adjust your risk based on the exposure to treatment. And when we do that, we’re not seeing a difference in terms of rate of side effects like atrial fibrillation (AFib) or hypertension. Now, to be very clear, these are not planned or pre-planned analyses, these are post-hoc analyses. But we do it all the time in clinical trials, and for AFib and hypertension, for example, the risk with zanubrutinib in that arm seems pretty like the background risk for this patient population with the age and co-morbidities, and that's reflected in the control arm here. So, as I said, with the longer follow up, we're not seeing some of the adverse events that we remember from, for example, ibrutinib (Imbruvica; AbbVie, Janssen Biotech) like sudden cardiac deaths or major cardiac issues. The rates seem similar, number-wise and I think that's important for physicians and for patients. This is the 5-year follow-up, but zanubrutinib has been around even as an FDA-approved drug. It's good to see that the safety profile remains favorable with the with the 5-year follow up of the SEQUOIA trial.

Pharmacy Times: What are the mechanisms of action that contribute to the efficacy of zanubrutinib in CLL?

Shadman: Before we had the results of these perspective clinical trials, the hypothesis was that zanubrutinib was likely to be effective and even more effective than some of the other BTKis. Of course, in parenthesis, I would say that in the ALPINE trial we've shown that it's superior to ibrutinib. The reason is because of the receptor occupancy, the BTK occupancy with zanubrutinib, even with the pharmacological studies, was great. Even at the through levels, we had levels that were above the IC50 regardless of the schedule. As you know, zanubrutinib could be given as a BID dosing, which was the dosing that was used in the SEQUOIA trial. But in some of the other trials, and in practice, patients have the option of using once-a-day dosing and, with both schedules, we do see that the drug level remains above the IC50 consistently. With those, I'm not surprised to see that the efficacy looks better than chemotherapy. But there are some features that in my opinion are unique in this study. For example, the complete response (CR) rate; not something we're used to seeing with monotherapy BTKis, right?
If you look at the CR and the CRI rate with the SEQUOIA, it's now approaching 20%. So, 1 out of 5 patients who took zanubrutinib are in a complete remission. This is not something you see or expect to see. One out of 5 patients now in complete remission, and the number is getting better with the longer follow up.

We also see that the benefit of zanubrutinib over chemoimmunotherapy, in this case B-R is consistent irrespective of some of the high-risk features that CLL can have. For example, the IGHV mutation is important in CLL and in response to treatment to chemotherapy. We now see that zanubrutinib is superior to chemotherapy, not only in the unmutated IGHV population—that's a group that chemotherapy does not do well, so it's not surprising to see that zanubrutinib over-performed B-R—but with a longer follow-up, we showed that zanubrutinib is superior even in a mutated IGHV group. And with this follow up at ASH, we are confirming that that continues to be the case. The hypothesis that we had in terms of efficacy is now being evaluated in clinical trials, translating to something that we can measure clinically.

Cohort 2 of SEQUOIA is not being presented or was not presented at ASH 2024. However, from the prior analysis, we know that in patients in cohort 2 with del(17p), the PFS rate looks pretty similar in that group and that cohort and very similar to cohort 1, which are patients without del(17p). Overall, some of the conventional prognostic markers don't seem to impact zanubrutinib’s efficacy in the first line.

Pharmacy Times: How do the results of the SEQUOIA study help inform the optimal treatment sequence for CLL patients?

Shadman: When we think about first line options, BTKis are one, and the second option would be a time-limited therapy with venetoclax and obinutuzumab. For patients with high-risk features, with del(17p), with mutated P53, and maybe with patients with unmutated IGHV, these factors don't seem to impact the clinical efficacy of zanubrutinib. And there are many patients who decide to go with a BTKi therapy in the first line, so this data is important to show that monotherapy with a BTKi can result in high efficacy and could be safely used. So, adding more information to one of the two main options in the first line setting. I think that's extremely informative.

Pharmacy Times: What are ongoing research efforts to further optimize the use of BTKis in CLL, including potential combination therapies?

Shadman: There are many important studies, I’ll highlight a few. First, the question of, in patients who are taking other BTKis, and they have issues in terms of tolerance and whether or not zanubrutinib would be an option. We have the 215 study, which is another study we're presenting at ASH 2024. We're showing that patients who come off acalabrutinib (Calquence; AstraZeneca) because of adverse events can go on zanubrutinib and they do well. Again, this has been presented before, so that study is still ongoing and is something to think about. One of the most important efforts is to combine zanubrutinib with other agents and come up with a time-limited therapy, which seems to be the direction that the field is taking. Zanubrutinib in combination with a BCL-2 inhibitor would be great. From the same SEQUOIA trial, we had a arm D and a cohort that we combined zanubrutinib with venetoclax. However, we are also having data presented at ASH combining zanubrutinib with sonrotoclax (BeiGene). That's a new BCL-2 inhibitor. That combination shows high efficacy with high quality responses. This combination is now tested against the current standard of care, venetoclax end of obinutuizimab in the first-line setting. The CELESTIAL-TNCLL trial is the global, randomized phase 3 registration trial that just actually finished enrollment way ahead of time. The study combined zanubrutinib and sonrotoclax in the investigational arm versus the control arm of venetoclax and obinutuzimab (Gazyva; Genetech). The study just finished enrollment, we will need to wait for the results to be available in the next few years and, if positive, it could change the standard of care for first-line CLL. From what we know from the combination of zanubrutinib and sonrotoclax and the high CR rates, and very high rate of undetectable minimum residual disease (MRD), it will be a very interesting study to wait for the results. Many other studies are ongoing at different levels, at different institutions, combining zanubrutinib with antibodies and other drugs. In the next couple years, we'll get much more clinical data out of zanubrutinib combinations.

Pharmacy Times: Is there anything else that you would like to add?

Shadman: No, I just wanted to thank you again. I’m excited to have been part of this study and to show that the drug is an effective drug. Our patients who participate in the clinical trials enjoy when we share these results with them. They were part of the journey to get this drug approved and it’s a mutual benefit that the study and patients had. I highly encourage everyone to consider clinical trials and to participate in clinical trials. We still have a long way to go with CLL, until we cure it.