Ongoing Trial Evaluates Zanubrutinib in BTK-Intolerant B-Cell Malignancies

Ian W. Flinn, MD, PhD, discusses the adverse effects associated with BTK inhibitors in B-cell malignancies, as well as the design of an ongoing phase 2 study with zanubrutinib.

BTK inhibitors have become an important drug class in many B-cell malignancies, explained Ian W. Flinn, MD, PhD, who added that the next-generation inhibitor zanubrutinib (Brukinsa) could be an alternative option for patients who are intolerant of ibrutinib (Imbruvica) or acalabrutinib (Calquence).

“BTK inhibitors have taken a very prominent role in the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies,” said Flinn. “In CLL, we now have randomized trials that show that BTK inhibitors [should be considered] the frontline treatment of choice for patients.”

At the 2020 ASCO Virtual Scientific Program, Flinn presented a poster showcasing the ongoing phase 2 BGB-3111-215 trial (NCT04116437) evaluating zanubrutinib in patients with previously treated B-cell malignancies intolerant to prior ibrutinib or acalabrutinib.

Investigators plan to enroll approximately 60 patients with CLL, small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma, or marginal zone lymphoma intolerant of prior BTK inhibition whose treatment-emergent adverse effects (TRAEs) resolve to grade 1 or lower prior to initiating treatment with zanubrutinib.

The primary end point of the study is the recurrence and change in severity of TRAEs with zanubrutinib compared with ibrutinib and/or acalabrutinib, according to Flinn.

Enrollment, which is currently underway, will span across 30 primary community medical centers from across the United States.

In an interview with OncLive, Flinn, director of lymphoma research and principal investigator at Sarah Cannon Research Institute, and director of the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center, discussed the AEs associated with BTK inhibitors in B-cell malignancies, as well as the design of the ongoing phase 2 study with zanubrutinib.

OncLive: What are some of the most common reasons patient discontinue treatment with ibrutinib?

Flinn: The most common reasons for ibrutinib discontinuation are arthralgias, which happen in about 40% of patients. Arthralgias are joint pain and other aches and pains; some patients cannot tolerate them. Abnormal heart rhythms and atrial fibrillation occur in up to 15% of patients [treated with ibrutinib] depending on their age and the study that was conducted. Bleeding is another major reason for discontinuation. Although major bleeding occurs in a small minority of patients, when it does happen, it is reason to stop ibrutinib.

Could you shed light on zanubrutinib and what distinguishes the agent from earlier-generation BTK inhibitors?

Zanubrutinib is a specific inhibitor of BTK. It has less inhibition of off-target kinases. As a consequence, the hypothesis is that it will have less of these AEs, such as arthralgias, atrial fibrillation, and bleeding.

Are there any data to support the use of zanubrutinib after ibrutinib? Is there any concern that BTK after BTK is not going to be effective?

I don’t think zanubrutinib would work necessarily if a patient had failed ibrutinib or acalabrutinib. If the reason they are [starting another drug] and coming off of [ibrutinib or acalabrutinib] is because they are progressing, then I don’t think there is rationale to give zanubrutinib. However, beyond progression, the number 1 reason why patients discontinue treatment with BTK inhibitors is intolerance.

In that case, there’s good rationale to think that patients who are intolerant to ibrutinib or acalabrutinib might tolerate zanubrutinib.

Could you elaborate on the design of the ongoing phase 2 trial and some of the key inclusion and exclusion criteria?

It is a simple trial. Patients who have been on and are intolerant of ibrutinib or acalabrutinib come off of those agents. When the AE they experienced gets back down to grade 1 or less, they are then eligible to go on to zanubrutinib. The primary end point is essentially whether the same intolerance reoccurs or not. 

The hypothesis is that these AEs will not reoccur, which will allow patients to continue on zanubrutinib.

How is intolerance being defined in the study?

There are a variety of different categories, but intolerance is basically defined as bad joint pain, cardiac arrhythmia, or bleeding to the point where a patient’s physician does not think they can remain on that drug. If the patient has to come off therapy, they may be eligible for this trial.

Is there other ongoing or planned research with BTK inhibitors that you would like to highlight?

There are many ongoing trials with zanubrutinib and other BTK inhibitors. The biggest issue we have currently in these diseases is which BTK inhibitor is better? There are head-to-head trials comparing zanubrutinib with ibrutinib and acalabrutinib with ibrutinib to better understand how the efficacy and AE profiles line up. Many people think that these drugs are fairly similar in their efficacy, but because some patients have to come off treatment—most prominently with ibrutinib—that cuts into the efficacy because patients are no longer on therapy. Perhaps that is where the differences will be [most evident].


  1. Flinn I, Shadman M, Freeman B, et al. Trial in progress: a phase 2, multicenter, single-arm study of zanubrutinib (BGB-3111) in patients with previously treated B-cell malignancies intolerant to prior treatment with ibrutinib. or acalabrutinib. J Clin Oncol. 2020;38(15 suppl):TPS8066. doi:10.1200/JCO.2020.38.15_suppl.TPS8066