Indirect comparison of eﬃcacy of zanubru�nib versus acalabru�nib in the treatment ofrelapsed/refractory mantle cell lymphoma
Bijal D. Shah*1, Swetha Challagulla2, Sheng Xu3, Rhys Williams2, Shijie Ren4, 5, Tushar Srivastava4, Raju
Gautam4, Keri Yang2
1Moffitt Cancer Center, Tampa, FL, United States of America, 2BeiGene USA, Inc., San Mateo, CA,

United States of America, 3BeiGene (Shanghai) Co., Ltd., Shanghai, China, 4ConnectHEOR, London,
United Kingdom, 5SCHARR, University of Sheffield, Sheffield, United Kingdom
Background: Mantle cell lymphoma (MCL) is a dis�nct subtype of B-cell non-Hodgkin lymphoma
characterized by its aggressive nature and poor prognosis. The treatment landscape forrelapsed/refractory (R/R) MCL has evolved signiﬁcantly with the introduc�on of targeted therapies,
oﬀering new hope for pa�ents. Zanubru�nib and acalabru�nib are second-genera�on Bruton tyrosine
kinase inhibitors (BTKis) that have demonstrated improved safety proﬁles vs ﬁrst-genera�on BTKiibru�nib in clinical trials. Zanubru�nib and acalabru�nib have demonstrated clinical beneﬁts inseparate single-arm trials in pa�ents with R/R MCL and are approved therapies for R/R MCL. However,there is a lack of evidence on their compara�ve eﬃcacy.
Aims: To assess the compara�ve eﬃcacy of zanubru�nib vs acalabru�nib in pa�ents with R/R MCL, in
the absence of head-to-head clinical trials, using simulated treatment comparison (STC).
Methods: The clinical trials of zanubru�nib and acalabru�nib were iden�ﬁed through the literature
review and comprised BGB-3111-206 (NCT03206970), BGB-3111-AU-003 (NCT02343120), and ACE-LY004 (NCT02213926). These trials were reviewed thoroughly for the popula�on, study design,interven�on, and outcomes to assess the comparability for indirect treatment comparison (ITC). The
eﬃcacy of zanubru�nib was informed by the pooled individual pa�ent-level data (n=123) from BGB3111-206 and BGB-3111-AU-003 trials, and the eﬃcacy of acalabru�nib was informed by the publishedaggregated data of ACE-LY-004 (n=124). As these trials do not have a common comparator, anunanchored ITC was conducted using STC method. A Cox regression model was used to adjust thepopula�on for poten�al prognos�c factors or eﬀect modiﬁers, which were iden�ﬁed from literatureand validated with clinical experts. These covariates included prior lines of therapy and prior auto stem
cell transplanta�on, lactate dehydrogenase concentra�on, Eastern Coopera�ve Oncology Group
performance status ≥2, simpliﬁed Mantle Cell Lymphoma Interna�onal Prognos�c Index, age and sex,
tumor bulk, race, bone marrow involvement, disease stage, and extranodal disease. The eﬃcacy
outcomes of interest included inves�gator-assessed progression-free survival (PFS), overall survival(OS), and overall response rate (ORR). Hazard ra�o (HR) for PFS and OS, and odds ra�o (OR) for ORR
were es�mated with 95% conﬁdence intervals (CIs). All covariates were adjusted in the base caseanalysis. Sensi�vity analyses were performed using a subset of all covariates.
Results: The results of the base case analysis showed that treatment with zanubru�nib was associatedwith signiﬁcantly greater PFS (HR, 0.57 [95% CI, 0.35-0.94]; P=0.0272) and OS (HR, 0.43 [95% CI, 0.230.82]; P=0.0105) compared with acalabru�nib in pa�ents with R/R MCL (Table 1). Similarly, the ORR
was observed to be higher with zanubru�nib vs acalabru�nib (OR, 2.05 [95% CI, 0.72-5.84]; P=0.1798)
but did not achieve the signiﬁcance level. The results of sensi�vity analyses (models without race andwithout age) yielded consistent results.
Summary/Conclusion: The results of this simulated treatment comparison demonstrated thatzanubru�nib had signiﬁcantly beter PFS and OS compared with acalabru�nib in the treatment ofpa�ents with R/R MCL a�er adjus�ng for a large set of covariates. In the absence of a head-to-headEHA 2024

comparison trial, this study provides important insights about the compara�ve eﬃcacy of zanubru�niband acalabru�nib in the R/R MCL se�ng.

Table 1: Results of STC comparing zanubru�nib vs acalabru�nib for eﬃcacy outcomesPFSOSORR

HR (95% CI, P-value)
0.57 (0.35-0.94,HR (95% CI, P-value)
0.43 (0.23-0.82,

OR (95% CI, P-value)
2.05 (0.72-5.84,P=0.0272)

P=0.0105)

P=0.1798)

Sensi�vity analysis 1

0.62 (0.39-0.98,

0.42 (0.25-0.70,

1.48 (0.57-3.82,(Model 1 without race)

P=0.0418)

P=0.0009)

P=0.4165)

Sensi�vity analysis 2

0.58 (0.35-0.97,

0.48 (0.25-0.94,

2.19 (0.73-6.52,(Model 1 without age)

P=0.0388)

P=0.0335)

P=0.1606)

Base case and sensi�vity analyses
Base case analysis(adjusted* for all covariates / Model 1)*Popula�on adjusted for covariates including age, sex, race, ECOG performance status, sMIPI, LDH concentra�on, tumor bulk,bone marrow involvement, disease stage, extranodal disease, prior lines of therapy / prior auto SCT.
CI, conﬁdence interval; ECOG, Eastern Coopera�ve Oncology Group; HR, hazard ra�o; LDH, lactate dehydrogenase; OR, odds
ra�o; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; sMIPI, simpliﬁed Mantle Cell Lymphoma
Interna�onal Prognos�c Index; SCT, stem cell transplanta�on; STC, simulated treatment comparison.

EHA 2024