Zanubrutinib Demonstrates Efficacy and Safety in Acalabrutinib-Intolerant Patients with B-Cell Malignancies

Updated results from the ongoing phase 2 BGB-3111-215 trial (NCT04116437) showed that zanubrutinib (Brukinsa) provided clinically meaningful benefit to a large majority of efficacy-evaluable patients with B-cell malignancies who were intolerant to acalabrutinib (Calquence). Findings were presented during the 2022 ASH Annual Meeting.

Among 18 efficacy-evaluable patients, the disease control rate (DCR), defined as stable disease or better, was 94% (95% CI, 72.7%-99.9%). The overall response rate (ORR) was 61% (95% CI,35.7%-82.7%). The median time to best overall response and the median time to first overall response were both 3 months (range, 2.7-11.1).

Eligible patients in cohort 2 (n = 21) in BGB-3111-215 had been previously treated for chronic lymphocytic leukemia (n = 13), small lymphocytic leukemia (n = 2), mantle cell lymphoma (n = 1), marginal zone lymphoma (n = 2), and Waldenström macroglobulinemia (n = 3), and were intolerant to a prior BTK inhibitor. Patients in cohort 2 were intolerant to acalabrutinib and received zanubrutinib at a dose of 160 mg twice daily (67%) or 320 mg once a day (33%). Patients who were intolerant only to ibrutinib were enrolled to cohort 1 (n = 57) and were not included in this analysis.

Inclusion criteria for acalabrutinib intolerance that led to discontinuation of treatment was defined as: grade 1 or greater nonhematologic toxicity for more than 7 days or of any duration with over 3 recurrent episodes, grade 3 or higher nonhematologic toxicity for any duration, grade 3 neutropenia with fever or infection, grade 4 hematologic toxicity that was persistent until discontinuation of BTK inhibitor, inability to use acid-reducing or anticoagulant agents due to the BTK inhibitor, and resolution of a grade 2 or higher BTK inhibitor to grade 1 or below or baseline with resolution of grade 1 toxicities to 0 or baseline before beginning zanubrutinib treatment. Exclusion criteria solely included disease progression during the previous treatment with a BTK inhibitor.

The primary objective of the study was evaluating safety based on the recurrence and change in severity of AEs associated with acalabrutinib. Secondary objectives included ORR, DCR, progression-free survival, and patient-reported outcomes. Previous findings from the trial demonstrated that zanubrutinib was well tolerated in patients with B-cell malignancies who were intolerant to ibruntinib (Imbruvica) and/or acalabrutinib.

Safety results from the analysis demonstrated that in cohort 2,75% of acalabrutinib any grade adverse events (AEs) did not occur during zanubrutinib treatment and there were no acalabrutinib AEs that recurred at a high severity. Additionally, 67% of patients did not experience any recurrence of previously experienced AEs.

The cumulative exposure to acalabrutinib prior to discontinuation was 4.6 months, however 67% of patients did not experience a recurrence of prior acalabrutinib intolerance events after a median of 7.6 months of zanubrutnib treatment. When examining AE recurrence, 19% of patients experienced the same grade, 6% experienced a lower grade, and 75% of patients had no recurrence at all when treated with zanubrutnib.

With a median follow-up of 8.6 months (range, 0.1- 23.8), the median duration of zanubrutinib treatment was 7.6 months (range, 0.1-23.8). Most patients (81%) remain on the study with 76% remaining on treatment. Five (24%) patients discontinued treatment because of an AE, 1 because of disease progression, and 2 due to withdrawal by patient. One patient died from progressive disease.

Two of the patients that discontinued treatment experienced recurrence of a prior acalabrutinib intolerance event and 52% of patients had a dose interruption due an AE while 14% had an event that led to dose reduction. Out of 3 patients who experienced the same intolerance event with ibrutinib and acalabrutinib treatments, 2 did not have a recurrence on zanubrutinib and one patient had a lower grade recurrence.

When examining the kinase selectivity of zanubrutinib, ibrutinib, acalabrutinib, and acalabrutinib’s major metabolite (M27), zanubrutinib had the highest selectivity. Inhibition at rates of 50% of greater were recorded in 7, 17, 15, and 23 kinases, respectively, of the 370 tested. The treatment of B-cell malignancies with BTK inhibitors can be limited by AEs but the investigators noted that zanubrutinib was “designed to maximize BTK occupancy and minimize off-target kinase binding and associated AEs.”

Patients in cohort 2 had a median age of 73 years (range, 51-87) and had received a median of 2 (range, 1-6) prior BTK treatments. The prior BTK inhibitor therapies were ibrutinib monotherapy, ibrutinib combination therapy, acalabrutinib monotherapy, and acalabrutinib combination therapy with patients receiving the treatments at rates of 48%, 4.8%, 95%, 4.8% of the treatments, respectively. The median acalabrutinib exposure was 4.6 months (range, 0.2-26.9).

Investigators noted that there were no decreases in atrial fibrillation, anemia, or thrombocytopenia/platelet count following treatment. The most common AEs of any grade were fatigue (29%), diarrhea (24%), hypertension (24%), arthralgia (19%), cough (19%), myalgia (19%), and COVID-19 (14%). Nineteen percent of patients experienced a grade 3 or higher AE with 2 patients experiencing a decrease in neutrophil count, which was the only grade 3 or higher AE that occurred in more than 1 patient.

Reference

Shadman M, Flinn IW, Kingsley EC, 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