Zanubrutinib Delivers Durable Disease Control in Relapsed/Refractory MZL

Stephen Opat, MBBS

Zanubrutinib (Brukinsa) sustained high response rates and led to durable disease control with low incidence of hypertension and atrial fibrillation in patients with relapsed/refractory marginal zone lymphoma (MZL), according to findings from the final analysis of the phase 2 MAGNOLIA trial (NCT03846427).

“B-cell receptor signaling mediated through BTK is a critical pathway in marginal zone lymphoma pathogenesis,” said study author Stephen Opat, MBBS, director of Clinical Haematology at Monash Health and head of the Department of Haematology, School of Clinical Sciences at Monash Health, Monash University, in Australia, while presenting the data at the 2022 American Society of Hematology (ASH) Annual Meeting.

Preliminary findings from MAGNOLIA led to the Food and Drug Administration (FDA) approval of zanubrutinib in 2021.

Now, data from a median follow-up of 28 months and a median treatment duration of 24.2 months show that the IRC-assessed overall response rate (ORR) was 68.2% (n = 45; 95% CI, 55.6-79.1)—including a 25.8% complete response (CR) rate (n = 17)—in the overall study population, which included 66 patients with relapsed/refractory MZL that was treated with at least 1 CD20-directed regimen.

ORR was 64.0%, 76.0%, 66.7%, and 50.0% for patients with extranodal, nodal, splenic, and unknown subtypes of MZL, respectively.

Opat noted that across all data analyses, responses occurred “fairly fast,” at 2.8 months, and “were seen regardless of age, subtype, … disease stage, presence or absence of bone marrow involvement, whether relapsed or refractory.”

CR rates were 40.0% for those with extranodal disease; 20% for nodal disease; 8.3% for splenic disease; and 25.0% for those with an unknown subtype.

A sensitivity analysis using only CT-based criteria found and ORR and CR of 66.7% (95% CI, 54.0-77.8) and 24.2%, respectively.

The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) rates were not yet determined at the data cut-off.

According to independent review, at the 24-month mark, 72.9% of patients were still responding to treatment (95% CI, 54.4-84.9), with a PFS rate of 70.9% (95% CI, 57.2-81.0) and an OS rate of 85.9% (95% CI, 74.7-92.4).

At the time of study completion, 45.6% of patients (n = 31) benefitted from rolling over to a long-term extension (LTE) study of zanubrutinib.

A total of 35.3% (n = 24) discontinued treatment with the BTK inhibitor due to investigator-assessed disease progression; 7.4% patients (n = 5) stopped treatment due to adverse events (AEs); 2.9% (n = 2) required prohibited medications; and 1.5% (n = 1) withdrew consent.

While all patients experienced at least one AE, no new safety signals were observed with zanubrutinib, Opat explained.

The most common treatment-emergent AEs that occurred in 10% or more of patients were: bruising (23.5%), diarrhea (22.1%), constipation (17.6%), arthralgia (14.7%), pyrexia (14.7%), upper respiratory tract infection (13.2%), abdominal pain and back pain (each 11.8%).

Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common grade 3 or higher AEs. There were five (7.4%) patient deaths due to unrelated AEs: 1 from COVID-19 pneumonia; 1 from acute myeloid leukemia in a patient who had prior alkylating agent exposure; 1 myocardial infarction in a patient with preexisting coronary artery disease; and 1 patient from septic encephalopathy.

Three patients (4.4%) experienced hypertension, and 1 patient (1.5%) experienced atrial fibrillation and atrial flutter. None of these AEs led to treatment discontinuation.

Additionally, 1 patient (1.5%) experienced grade 3 gastrointestinal hemorrhage while receiving rivaroxaban for pulmonary embolism. This patient fully recovered and rolled over to the LTE study.

“Zanubrutinib is a potent and highly-specific next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, which are thought to be responsible for some of the side effects of other drugs in this class,” Opat concluded.

Reference

Opat S, Tedeschi A, Hu B, et. al. Long-Term Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory (R/R) Marginal Zone Lymphoma (MZL): Final Analysis of the Magnolia (BGB-3111-214) Trial. Presented at: 64th Annual ASH Meeting and Exposition. Dec. 10-13, 2022. New Orleans, Louisiana. Abstract 234.