Findings from a retrospective cohort study revealed that second- or third-line treatment with zanubrutinib (Brukinsa) was associated with improved real-world overall survival (OS) and time to next treatment (TTNT) compared with ibrutinib (Imbruvica) in patients with relapsed/refractory mantle cell lymphoma (MCL).1 Trends for improved OS and TTNT were also observed for zanubrutinib compared with acalabrutinib (Calquence).
In an inverse probability of treatment weighting (IPTW) adjusted model, zanubrutinib produced a statistically significant improvement in OS compared with ibrutinib (HR, 0.63; 95% CI, 0.42-0.96; P = .03) and a numerically greater TTNT (HR, 0.75; 95% CI, 0.55-1.04; P = .08). Notably, trends for improved OS (HR, 0.77; 95% CI, 0.53-1.11; P = .20) and TTNT (HR, 0.91; 95% CI, 0.68-1.22; P = .50) were reported for zanubrutinib vs acalabrutinib.
Among the overall study population (n = 698), second- or third-line treatment with a covalent BTK inhibitor produced a median OS of 30.4 months (95% CI, 24.7-36.1). The median OS was 28.8 months (95% CI, 23.7-not reached [NR]) for patients treated with zanubrutinib (n = 135), 29.2 months (95% CI, 22.9-36.5) for patients treated with acalabrutinib (n = 342), and 29.3 months (95% CI, 21.1-39.1) for those given ibrutinib (n = 221).
The overall median TTNT was 11.5 months (95% CI, 10.0-13.5), with values of 16.8 months (95% CI, 11.1-23.2) for zanubrutinib, 11.9 months (95% CI, 9.2-14.6) for acalabrutinib, and 9.8 months (95% CI, 7.6-13.1) for ibrutinib.
“Patients with relapsed/refractory MCL treated with covalent BTK inhibitor monotherapies at national oncology centers in the United States had longer real-world OS with second/third-line zanubrutinib compared with second/third-line ibrutinib, and trends favoring improved real-world TTNT for second/third-line zanubrutinib compared with second/third-line ibrutinib and second/third-line acalabrutinib,” lead study author Tycel Phillips, MD, and colleagues wrote in a publication of the data. “Future research is warranted to identify factors influencing use of zanubrutinib and acalabrutinib, reasons for differences in real-world TTNT and real-world OS across covalent BTK inhibitors, and reasons for changing between covalent BTK inhibitors.”
Phillips is an associate professor in the Division of Lymphoma of the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.
How was the retrospective cohort study conducted?
Real-World Study of Covalent BTK Inhibitor Outcomes in R/R MCL
- A retrospective real-world study found that zanubrutinib was associated with significantly longer OS than ibrutinib in patients with relapsed/refractory MCL treated with a covalent BTK inhibitor in the second- or third-line setting.
- Patients receiving zanubrutinib also experienced numerically longer time to next treatment compared with both ibrutinib and acalabrutinib.
- Researchers noted that treatment discontinuation was most often driven by disease progression or toxicity, and they called for further studies to better understand differences among covalent BTK inhibitors in real-world practice.
When the FDA granted accelerated approval to zanubrutinib for the treatment of adult patients with MCL who received at least 1 prior therapy in November 2019, it marked the third covalent BTK inhibitor approved for this patient population, joining ibrutinib and acalabrutinib.2
Despite the approvals of the 3 BTK inhibitors, the 3 agents have not been compared in head-to-head prospective studies in patients with relapsed/refractory MCL, and real-world data on treatment patterns and outcomes with covalent BTK inhibitors in relapsed/refractory MCL remain scarce.1 As such, this real-world study sought to evaluate real-world characteristics and utilization patterns of these BTK inhibitors within United States practice, along with examining efficacy and reasons for treatment discontinuation.
Patient data were gathered from the Flatiron Health database, with investigators identifying patients who were diagnosed with MCL on or after January 1, 2011, and started second-line treatment on or after January 1, 2018. Patients needed to be treated in the second- or third-line setting with zanubrutinib, acalabrutinib, or ibrutinib. Patients who received any treatment with a BTK inhibitor prior to BTK inhibitor monotherapy in the second or third line were excluded. The data cutoff was March 31, 2024.
Investigators compiled data on baseline demographic and clinical characteristics, real-world treatment patterns, and clinical outcomes. Among the 1377 patients with relapsed/refractory MCL who received any therapy in the second line or beyond, 698 were included in the real-world study. In this population, the median age was 73 years (range, 34-85), and most patients were male (74%), White (78%), and not Hispanic or Latino (74%). The majority of patients received covalent BTK inhibitor monotherapy in the second line (76%) vs the third line (24%).
Disease subtypes included blastoid MCL (7.4%), pleomorphic MCL (3.2%), leukemic MCL (4.6%), and MCL not otherwise specified (85%). Stages at diagnosis comprised I (1.7%), II (3.6%), III (12%), IV (63%), and unknown/undocumented (19%). Eighteen percent of patients had bulky disease at diagnosis, and 61% of patients had an ECOG performance status of 0 or 1. Twelve percent of patients had documented TP53 status at baseline, and 35% of this group (n = 85) had TP53-positive disease.
What data were reported regarding treatment discontinuation?
For patients treated with covalent BTK inhibitor monotherapy in the second- or third-line, the most common reasons for treatment discontinuation comprised disease progression (30.1%), toxicity (11.5%), other (9.3%), noncancer-related medical issue (3.9%), cancer-related symptoms not attributed to treatment (1.6%), and patient request (1.2%). Reasons for discontinuation were not documented for 39.7% of patients who discontinued treatment. These rates were similar across the zanubrutinib, acalabrutinib, and ibrutinib subgroups.
Notably, 6.7% of patients switched to another covalent BTK inhibitor following initiation of initial second- or third-line treatment, with a median time to next covalent BTK inhibitor of 8 months (interquartile range, 4-21). Among the 4.4% of patients (n = 31) who switched from ibrutinib to acalabrutinib or zanubrutinib, the reasons for discontinuation that were most common were toxicity (61.3%) and disease progression (19.4%). Additionally, 1.7% of patients switched from acalabrutinib to zanubrutinib due to toxicity (58.3%) and progression (25.0%). Less than 5 patients switched from zanubrutinib to acalabrutinib or ibrutinib.
What limitations were reported from this real-world study?
Phillips and colleagues noted that limited sample size and follow-up for zanubrutinib limited the ability to interpret small differences in treatment patterns and effectiveness compared with earlier-approved covalent BTK inhibitors. Additionally, lack of certain data on factors such as comorbidities, specific variables, and loss to follow-up could have introduced bias due to misclassification and confounding.
References
- Phillips T, Di M, Miller TA, et al. Real-world comparative effectiveness of Bruton tyrosine kinase inhibitors in relapsed/refractory mantle cell lymphoma. Blood Adv. 2026;10(5):1457-1468. doi:10.1182/bloodadvances.2025017160
- FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. FDA. November 14, 2019. Accessed May 11, 2026. https://www.prnewswire.com/news-releases/fda-approves-therapy-to-treat-patients-with-relapsed-and-refractory-mantle-cell-lymphoma-supported-by-clinical-trial-results-showing-high-response-rate-of-tumor-shrinkage-300958791.html
