Indirect Comparison Finds Zanubrutinib Associated With Better PFS, OS Than Acalabrutinib in MCL

An analysis based on separate trials of the Bruton tyrosine kinase (BTK) inhibitors zanubrutinib (Brukinsa; BeOne Medicines) and acalabrutinib (Calquence; AstraZeneca) found that zanubrutinib was associated with “significantly improved” progression-free survival (PFS) and overall survival (OS) for patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), according to results published in Leukemia & Lymphoma.¹

The simulated treatment comparison (STC) found that zanubrutinib was associated with improved PFS (HR, 0.57; 95% CI, 0.35-0.94; P = .0272) and OS (HR, 0.43; 95% CI, 0.23-0.82; P = .0105). Overall response rate (ORR) numerically favored zanubrutinib but did not reach statistical significance.

Bijal Shah, MD, MS | Image: Moffitt Cancer Center

An STC is one of several types of indirect analyses that can be used evaluate drugs in the same class that have not been compared in a clinical trial. Although the study authors note that clinical trials remain the gold standard, “the current study [provides] much needed evidence on the comparative efficacy of zanubrutinib and acalabrutinib in R/R MCL in the absence of head-to-head trials.”

BeOne Medicines supported the study.

According to the authors, led by Bijal Shah, MD, MS, of Moffitt Cancer Center, MCL is a subtype of B-cell non-Hodgkin lymphoma (NHL) that accounts for 5% of all NHL cases and affects about 20,000 patients in the United States. Although there have been very recent advances in clinical trials, MCL has had a poor prognosis, with a median OS of 3 to 5 years.²

Zanubrutinib and acalabrutinib are both second-generation BTK inhibitors that have shown efficacy and safety in single-arm trials involving patients with R/R MCL.¹ The authors cited single-arm trial data for zanubrutinib showing an ORR of 84% with a complete response (CR) of 78% over a median of 35.3 months, compared with ORR of 81.5% and CR of 47.6% over a median of 38.1 months for acalabrutinib. But lacking comparative effectiveness data, the authors selected an STC approach because it is “particularly well-suited for settings with limited patient data, such as MCL.”

Study authors started with 10 potential trials and found 3 met criteria for the analysis; excluded trials evaluated untreated MCL, use of the study drugs in combinations, or were ongoing in nature. The team then performed the 3-part process of the STC with the trial data extracted from the 3 studies. “Overall, except for a few differences, all 3 studies had sufficient similarities to allow for comparison,” they wrote. “The differences that were anticipated to influence the results were adjusted in the analyses where feasible.”

The authors made note of some differences between the trials and how they accounted for them. “The patients in the zanubrutinib trials appeared to be younger,” they wrote, with a smaller share of the zanubrutinib patients being younger than 65 years. “One of the 2 trials of zanubrutinib was conducted in China only and another had most patients from Australia and New Zealand. Sensitivity analyses conducted by excluding the covariates of age and race indicated no impact of these covariates on outcomes. Sensitivity analyses excluding the covariates of age and race demonstrated that these variables did not influence the treatment outcomes.”

There were also some differences in practice patterns based on where patients lived, with more US patients having received autologous stem cell transplant, and more of these patients had been enrolled in the acalabrutinib trial.

Some information was not available. “Several studies have shown the poor prognostic impact of tumor protein p53 (TP53) gene mutation and Ki-67 index in patients with MCL,” the authors noted. “Due to the unavailability of baseline data on the covariates of TP53 mutation and Ki-67 index in the acalabrutinib trial, these prog­nostic variables were not adjusted for in our analysis.”

The authors reviewed prior statistical analyses that compared the 2 BTK inhibitors with other therapies and noted that no safety comparison was performed, but that meta-analyses may offer better insight.

In conclusion, the authors wrote that zanubruti­nib “had significantly better PFS and OS versus acal­abrutinib in the treatment of patients with R/R MCL after adjusting for a large set of covariates.” With head-to-head trials unlikely to be performed, the STC “may support evidence-based treatment decisions and optimize care for patients with this disease, they said.

References

1. Shah B, Challagulla S, Xu S, et al. Zanubrutinib versus acalabrutinib indirect treatment comparison in relapsed or refractory mantle cell lymphoma. Leuk Lymph. Published September 1, 2025. doi:10.1080/10428194.2025.2541911

2. Abutalib SA, Fenske TS. Mantle cell lymphoma: front-line therapy. The ASCO Post. March 25, 2024. Accessed September 12, 2025. https://ascopost.com/issues/march-25-2024/mantle-cell-lymphoma-front-line-therapy