Matching-Adjusted Indirect Comparison of Zanubrutinib Versus Real-World
Chemoimmunotherapy or Chemotherapy in Relapsed/Refractory Marginal Zone Lymphoma

P1123

Renata Walewska,1 Kaijun Wang,2 Caitlin Smare,3 Ina Zhang,4 Leyla Mohseninejad,5 Silvy Mardiguian,6 Sam Keeping7
1University Hospitals Dorset, Department of Haematology, Bournemouth, UK; 2BeiGene USA, Inc, San Mateo, CA, USA; 3PRECISIONheor, London, UK; 4PRECISIONheor, Oakland, CA, USA;
5
BeiGene Netherlands B.V., Schiphol, The Netherlands; 6BeiGene, London, UK; 7PRECISIONheor, Vancouver, British Columbia, CanadaINTRODUCTION

R ESULTS• Marginal zone lymphoma (MZL), a form of non-Hodgkin lymphoma (NHL), can bedifficult to treat due to its rarity and range of clinical presentation• Before matching, the zanubrutinib population consisted of slightly younger, moreheavily pretreated patients, with a higher proportion who were refractory and who
on average had a longer time since diagnosis than the HMRN cohort• Zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, has recently been
approved for the treatment of relapsed/refractory (R/R) MZL in the European Union(EU) and United States (US) based on two phase 2 single-arm trials, MAGNOLIA(NCT03846427) and BGB-3111-AU-003 (NCT02343120)• Two previous matching-adjusted indirect comparisons (MAICs) have shown
zanubrutinib to be more efficacious in terms of progression-free survival (PFS) vs bothibrutinib (PCYC-1121) and rituximab (CHRONOS-3) based on data from clinical trials1,2• In the absence of head-to-head randomized controlled trials comparing zanubrutinibvs other treatment choices, unanchored indirect treatment comparisons can beutilized to estimate relative treatment effects• Convergence was achieved for all the logistic propensity score models resulting
in baseline characteristics that were balanced between the treatment groups after
matching (Table 1); the effective sample size (ESS) was 38 (a 56% reduction from asample of 86)• Results from the MAIC (with unadjusted comparisons also presented for informative
purposes only) are reported in Table 2

Zanubrutinib(MAGNOLIA & BGB-3111-AU-003 pooled)

Characteristic• This study aimed to estimate the comparative efficacy of zanubrutinib vs CIT,immunotherapy, or chemo for the treatment of patients with R/R MZL by conducting
a MAIC with data from the single arm trials of zanubrutinib and real-world data ofCIT, immunotherapy, or chemo use

Number of priortherapies, %Figure 1. MAIC of PFS with Zanubrutinib vs CIT, immunotherapy, or Chemo• Given a limited number of large clinical trials investigating repeat CIT, immunotherapy,or chemo in R/R MZL settings, an MAIC utilizing real-world evidence can beconsidered as appropriate and informative

1.00• To increase comparability of the populations, this study identified a subset of patientsfrom the HMRN cohort most aligned with the inclusion and exclusion criteria of thezanubrutinib trials

0.75

Weighted,
ESS=38

n=90

44.2

78.9

78.9

2

30.2

18.9

18.9

>2

25.6

2.2

2.2

30.1

25.6

25.6

Refractory to last therapy, %• While patient factors considered to have the largest impact on prognosis were adjusted
for in the analyses, residual bias from other unbalanced confounding variables remains apossibility
0.50• The precision of MAIC estimates is contingent on the degree of patient overlap acrossthe included studies; this can be observed in the adjusted models, whereby a large
reduction from the original sample size was observed• No comparison of safety outcomes was performed as these were not available from theHMRN registry

0.25

POD24, %

44.7

51.1

51.1

Data Sources

Mean age, years

68.0

73.3

73.3

• Individual patient-level data from 86 efficacy-evaluable patients enrolled in MAGNOLIA
and BGB-3111-AU-003 trials were used to inform the zanubrutinib treatment group3,4Time since diagnosis≥ median, %• All patients in the HMRN cohort were enrolled from 2014 onward, had an Eastern
Cooperative Oncology Group Performance Status (ECOG PS) ≤2 at entry into theregistry, and were previously treated with an anti-CD20-based therapy, in line with
the inclusion and exclusion criteria of MAGNOLIA and BGB-3111-AU-003 trials• All patients in the HMRN cohort were treated with CIT, immunotherapy, or chemo
alone; the most commonly used treatments being bendamustine + rituximab (30%),
rituximab monotherapy (13%), and rituximab, cyclophosphamide, vincristine, andprednisolone (11%)

Statistical Analysis• Logistic propensity score models were used to estimate weights for the pooled
population of patients from MAGNOLIA and BGB-3111-AU-003 such that meanbaseline characteristics matched those in the HMRN cohort• Prespecified characteristics for matching were confirmed by clinical experts and arepresented in order of importance in Table 1• As patients receiving chemo alone were anticipated to have worse outcomes thanthose receiving CIT or immunotherapy, a sensitivity analysis was performed whereby
17 patients treated with chemo only were excluded from the model• Relevant outcomes were PFS and overall survival (OS); PFS was assessed by anindependent review committee in the zanubrutinib trials and disease progression
data in the HMRN cohort was collected from medical records• Cox proportional hazards models were used to estimate relative treatment effects interms of hazard ratios (HRs) and their 95% confidence intervals (CIs)• Leave-one-out analyses were performed, whereby one covariate at a time wasomitted from the model to explore their individual impact on the treatment effectestimates

Unadjusted HR: 0.47 (0.29–0.76), P=.0019
Adjusted HR: 0.30 (0.15–0.63), P=.0014

Zanubrutinib, weighted

0.00
0612182430

3642485460– The adverse events from zanubrutinib were predominantly mild in nature with only
temporary interruptions in treatment and with no treatment-related discontinuation,dose reduction, or fatality, with the exception of one patient from BGB-3111-AU-003

Time, months
Number at risk

65.1

50.0

50.0

POD24, progression of disease within 24 months of treatment initiation.

Table 2. Results of Indirect Treatment Comparisons
Zanubrutinib
n/ESS

ModelPFS HR (95% CI)
P value

OS HR (95% CI)
P value

860.47 (0.29-0.76)
P<.01635143402724171210786655950

45942220383030

2420

421110Figure 2. MAIC of OS with Zanubrutinib vs CIT, immunotherapy, or Chemo

2. Thieblemont C, et al. Hemasphere. 2023;7(suppl):e10013c4.
3. Opat S, et al. Clin Cancer Res. 2021;27(23):6323-6332.

1.00

4. Phillips T, et al. Blood Adv. 2022;6(11):3472-3479.
5. HMRN. The Clinical Management and Outcome of Marginal Zone
Lymphoma (MZL) with a Focus on Relapsed/Refractory Disease: A Report fromthe Haematological Malignancy Research Network. Updated February 24, 2024.
Accessed March 20, 2024. https://hmrn.org/publications/reports

0.34 (0.19-0.61)
P<.01
0.75

MAIC (all covariates)

38

0.30 (0.15-0.63)
P<.01

0.23 (0.10-0.50)
P<.01

MAIC (excluding number of priorlines)

49

0.48 (0.26-0.87)
P=.02

0.37 (0.19-0.74)
P<.01

0.29 (0.15-0.57)
P<.01

0.22 (0.10-0.46)
P<.010.50

D ISC LO SU R E S

MAIC (excluding refractory tolast therapy)

39

MAIC (excluding age)52

0.31 (0.16-0.59)
P<.01

0.20 (0.09-0.43)
P<.0001

MAIC (excluding POD24)

39

0.29 (0.14-0.62)
P<.01

0.21 (0.09-0.45)
P<.01

HMRN

0.26 (0.14-0.51)
P<.01

0.24 (0.11-0.53)
P<.01

Zanubrutinib, weighted

MAIC (excluding time sincediagnosis)

41

Unadjusted
MAIC (all covariates)

8640

0.51 (0.31-0.83)
P<.01
0.28 (0.14-0.57)
P<.01

RW: Honoraria: Janssen, AstraZeneca, AbbVie, BeiGene; Advisory Board: Janssen,AstraZeneca, SecuraBio, AbbVie, BeiGene. KW, LM, and SM: Employment: BeiGene.
CS, IZ, and SK: Employment: PRECISIONheor; Research funding: BeiGene.

0.25

Zanubrutinib, unweighted
0.00
0Zanubrutinib vs CIT or immunotherapy (n=73)

61218

Unadjusted HR: 0.34 (0.19–0.61), P=.0004
Adjusted HR: 0.23 (0.10–0.50), P=.0002

2430

AC K N OW LE D G E M E N TS

3642485460

Time, months

0.37 (0.20-0.68)
P<.01
0.23 (0.10-0.49)
P<.01

REFERENCES
1. Thieblemont C, et al. J Clin Oncol. 2023;14(16_suppl):e19527.

Zanubrutinib vs CIT, immunotherapy, or chemo (n=90)
Unadjusted

90

Values in parentheses are 95% CIs.

Overall survival• Aggregate data from a comparable cohort of 90 patients treated with CIT,
immunotherapy, or chemo was identified from the Haematological Malignancy
Research Network (HMRN), a UK cancer registry5– In general, rituximab is known to be a well-tolerated treatment in lymphoma andbendamustine plus rituximab is considered the most toxic of the treatment basket byclinicians

HMRN
Zanubrutinib, unweighted

M ET H O D S

D ISC U SSIO NCIT, immunotherapy,or chemo (HMRN)

Unweighted,n=86• MAIC results suggest that zanubrutinib can be considered an effective alternative
to CIT, immunotherapy, or chemotherapy, adding to a body of evidence informing
the relative efficacy of treatment options in patients with R/R MZL• The leave-one-out analyses showed that removing any one of the characteristics did
not significantly alter the treatment effect estimates, though number of prior lines oftherapy had the largest impact

Table 1. Comparison of Patient Characteristics Before and After Matching1

O B J EC T IV E

• Zanubrutinib significantly reduced the risk of progression (Figure 1) and death(Figure 2) relative to CIT, immunotherapy, and chemo. Model results excluding
patients treated with chemo alone (ESS=40; 53% reduction) were consistent withthese findings

Progression-free survival• Patients with advanced disease are characterized by a continuing pattern of relapseand remission; current management for these patients generally involves utilizing
regimens shown to be effective in other indolent NHLs such as repeating or alternating
chemoimmunotherapy (CIT), immunotherapy alone, or chemotherapy (chemo) regimens

C O N C LU SIO N

Number at risk
9077645956

4642343025

19868380

74

69

36

14

844238

37

36

33

30

16

5333

1Values in parentheses are 95% CIs.

The authors thank the patients who participated in the MAGNOLIA andBGB-3111-AU-003 studies.
The authors also thank HMRN for granting access to valuable registry data, which
contributed to the findings presented in this abstract.
This study was sponsored by BeiGene. Editorial assistance was provided byPRECISIONheor, and supported by BeiGene.

Presented at EHA 2024; June 13-16, 2024; Madrid, Spain/Virtual Conference