Zanubrutinib Shows Superior Real-World Survival Outcomes Compared to Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
Key Insights
A retrospective cohort study of 698 patients demonstrated that zanubrutinib achieved significantly improved overall survival compared to ibrutinib in second- or third-line treatment of relapsed/refractory mantle cell lymphoma (search) (HR, 0.63; 95% CI, 0.42-0.96; P = .03).
Zanubrutinib also showed numerically longer time to next treatment compared to both ibrutinib and acalabrutinib, with median values of 16.8 months versus 9.8 months and 11.9 months, respectively.
The study represents the first real-world comparison of the three FDA-approved covalent BTK (search) inhibitors in this patient population, as head-to-head prospective trials have not been conducted.
A large retrospective study has revealed that zanubrutinib (Brukinsa) demonstrates superior real-world survival outcomes compared to ibrutinib (Imbruvica) in patients with relapsed/refractory mantle cell lymphoma (search) (MCL), providing the first comparative effectiveness data for the three FDA-approved covalent BTK (search) inhibitors in this challenging patient population.
Significant Survival Advantage for Zanubrutinib
The retrospective cohort study of 698 patients showed that zanubrutinib produced a statistically significant improvement in overall survival compared with ibrutinib in an inverse probability of treatment weighting (IPTW) adjusted model (HR, 0.63; 95% CI, 0.42-0.96; P = .03). Additionally, zanubrutinib demonstrated a numerically greater time to next treatment compared to ibrutinib (HR, 0.75; 95% CI, 0.55-1.04; P = .08).
When compared to acalabrutinib (Calquence), zanubrutinib showed trends for improved overall survival (HR, 0.77; 95% CI, 0.53-1.11; P = .20) and time to next treatment (HR, 0.91; 95% CI, 0.68-1.22; P = .50), though these differences did not reach statistical significance.
Real-World Treatment Outcomes
Among the overall study population receiving second- or third-line treatment with a covalent BTK (search) inhibitor, the median overall survival was 30.4 months (95% CI, 24.7-36.1). When analyzed by individual agents, the median overall survival was 28.8 months (95% CI, 23.7-not reached) for zanubrutinib-treated patients (n = 135), 29.2 months (95% CI, 22.9-36.5) for acalabrutinib-treated patients (n = 342), and 29.3 months (95% CI, 21.1-39.1) for ibrutinib-treated patients (n = 221).
The time to next treatment data revealed more pronounced differences between agents. The overall median time to next treatment was 11.5 months (95% CI, 10.0-13.5), with zanubrutinib achieving 16.8 months (95% CI, 11.1-23.2), acalabrutinib reaching 11.9 months (95% CI, 9.2-14.6), and ibrutinib showing 9.8 months (95% CI, 7.6-13.1).
Study Design and Patient Characteristics
The research utilized data from the Flatiron Health (search) database, identifying patients diagnosed with MCL on or after January 1, 2011, who started second-line treatment on or after January 1, 2018. Patients were required to receive zanubrutinib, acalabrutinib, or ibrutinib in the second- or third-line setting, with a data cutoff of March 31, 2024.
The study population had a median age of 73 years (range, 34-85), with most patients being male (74%), White (78%), and not Hispanic or Latino (74%). The majority received covalent BTK (search) inhibitor monotherapy in the second line (76%) versus 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%).
Treatment Discontinuation Patterns
For patients treated with covalent BTK (search) inhibitor monotherapy in the second- or third-line setting, the most common reasons for treatment discontinuation were disease progression (30.1%), toxicity (11.5%), and other reasons (9.3%). Notably, 39.7% of patients who discontinued treatment had undocumented reasons for discontinuation, and these patterns were similar across all three BTK inhibitor subgroups.
Approximately 6.7% of patients switched to another covalent BTK (search) inhibitor following initiation of their initial second- or third-line treatment, with a median time to next covalent BTK inhibitor of 8 months. Among patients who switched from ibrutinib to acalabrutinib or zanubrutinib (4.4% of patients), toxicity (61.3%) and disease progression (19.4%) were the most common reasons for discontinuation.
Clinical Implications and Study Limitations
Lead study author Tycel Phillips, MD, an associate professor in the Division of Lymphoma at City of Hope (search), and colleagues noted that this represents the first real-world comparison of these agents, as head-to-head prospective studies have not been conducted in patients with relapsed/refractory MCL.
The researchers acknowledged several limitations, including limited sample size and follow-up for zanubrutinib, which restricted the ability to interpret small differences in treatment patterns and effectiveness compared with earlier-approved covalent BTK (search) inhibitors. Additionally, lack of certain data on factors such as comorbidities and specific variables could have introduced bias due to misclassification and confounding.
The findings provide important real-world evidence supporting the clinical utility of zanubrutinib in relapsed/refractory MCL, particularly when compared to ibrutinib, and may inform treatment decision-making in this challenging patient population where limited comparative data previously existed.