Zanubrutinib Extends Treatment Duration in Acalabrutinib-Intolerant Patients With B-cell Malignancies


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Patients with B-cell malignancies who were intolerant to acalabrutinib experienced a longer treatment duration when subsequently receiving zanubrutinib.

Mazyar Shadman, MD, MPH

Mazyar Shadman, MD, MPH

Patients with B-cell malignancies who were intolerant to acalabrutinib (Calquence) experienced a longer treatment duration when subsequently receiving zanubrutinib (Brukinsa). Mazyar Shadman, MD, MPH, said this demonstrates the potential for patients with chronic lymphocytic leukemia (CLL), marginal zone lymphoma, Waldenström macroglobulinemia, and mantle cell lymphoma (MCL) to benefit from a second BTK inhibitor following treatment intolerance.

Data from the ongoing phase 2 BGB-3111-215 trial (NCT04116437) presented at the 2022 ASH Annual Meeting showed that acalabrutinib-intolerant patients with B-cell malignancies (n = 21) experienced a median treatment duration of 7.6 months (range, 0.1-23.8) with zanubrutinib compared with 4.6 months (range, 0.2-26.9) for acalabrutinib. Additionally, among 18 patients evaluable for efficacy, the disease control rate was 94% (95% CI, 72.7%-99.9%) and the overall response rate was 61% (95% CI, 35.7%-82.7%).

“We are fortunate in some histologies, such as CLL, to have different classes of drugs. However, for some other [histologies], we are limited in our options. It’s important to know that a class of drugs like BTK inhibitors can still be utilized,” Shadman said to OncLive®. “Just because a patient has intolerance to a first- or second-generation [BTK inhibitor], it doesn't mean that class is off the table as a therapeutic option.”

In the interview, Shadman, the lead study author, discussed the key findings on the use of zanubrutinib in acalabrutinib-intolerant patients, the importance of intolerance trials in patients with B-cell malignancies, and what these findings mean for these patient populations. Shadman is an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Center in Seattle, Washington.

OncLive®: Could you expand on the methods used in the BGB-3111-215 trial and the patients included?

Shadman: This is a single-arm study [enrolling] patients with different types of B-cell malignancies who were taking acalabrutinib, and because of intolerance issues, had to stop acalabrutinib.

This study aimed to see if these patients could tolerate zanubrutinib and still benefit from a BTK inhibitor. We previously published the initial results of the [cohort of patients who received prior treatment with] ibrutinib [Imbruvica]. For this presentation, we focused on acalabrutinib-intolerant patients who have different types of diagnosis including CLL, marginal zone lymphoma, Waldenström macroglobulinemia, and MCL.

Why did you choose to investigate zanubrutinib in patients who were intolerant to a previous BTK inhibitor?

BTK inhibitors are a very important class [of drugs] for different types of B-cell malignancies, and patients benefit from them. Unfortunately, intolerance is a common problem with ibrutinib. [Although intolerance] is not as common with acalabrutinib, as we use this agent longer, we are having patients who unfortunately must discontinue [treatment]. The idea is to be able to continue BTK inhibitor as a treatment option for patients, but with another novel agent that could potentially be better tolerated, which is in this case is zanubrutinib.

What were the key data?

The median time on zanubrutinib was longer than the median time on acalabrutinib prior to enrollment in the study. This is important because we know that most of the time, the incidence of adverse effects [AEs] goes up with longer exposure to the drug.

In this cohort of 21 patients, the median exposure time to acalabrutinib was 4.6 months, but the median exposure time to zanubrutinib was 7.6 months. Even with a longer follow-up on zanubrutinib, the majority of patients did not have recurrence of the AEs that they had on acalabrutinib. This means that a patient who, for example, came off acalabrutinib for muscle pain, joint pain, or hypertension was able to take zanubrutinib for [longer than] acalabrutinib. We also saw that there were no AEs at a higher grade.

The efficacy and disease control rate were, as expected, very promising. For this study, we did not include patients who had progression on prior acalabrutinib, so zanubrutinib was able to provide continued benefit from an efficacy standpoint.

What information can be gathered from intolerance trials such as this one?

Intolerance studies such as this are important. We now have several head-to-head trials comparing ibrutinib with next-generation BTK inhibitors, but intolerance studies answer a different question. When you compare 2 groups that are both unexposed to BTK inhibitors and look at the incidence of AEs, that’s a different question than having a cohort of patients who have already had AEs either on ibrutinib, or in this case, on a second-generation BTK inhibitor, acalabrutinib.

What we’re planning to do now is to continue enrollment on this study and expand the cohort of acalabrutinib-intolerant patients. We are looking at expansion of the sites that are participating, potentially from different areas of the world. By generating similar data from other agents, hopefully we'll have a better understanding of [how to assist] patients who had issues in terms of tolerance to other BTK inhibitors.


Shadman M, Finn IW, Kingsley ED, et. al. Zanubrutinib in acalabrutinib-intolerant patients (pts) with B-cell malignancies. Blood. 2022;140(suppl 1):3655-3657. doi:10.1182/blood-2022-159726

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