Zanubrutinib Versus Acalabrutinibin B-cell Malignancies: An Adverse
Event-Based Economic Analysis
Talha Munir,1 Vincent Levy,2 Leyla Mohseninejad,3 Tushar Srivastava,4 Anurag Gupta,5Raju Gautam,4 Keri Yang,6 Rhys Williams,6 Shouhao Zhou,7 Yucai Wang8
1Leeds Teaching Hospital NHS Trust, Leeds, West Yorkshire, UK; 2Hôpital Avicenne, AP-HP et Université Sorbonne, Paris Nord, France; 3BeiGene Netherlands

B.V., Schiphol, the Netherlands; 4ConnectHEOR, London, UK; 5ConnectHEOR, Delhi, India; 6BeiGene USA, Inc, San Mateo, CA, USA; 7Division of Biostatistics
and Bioinformatics, Penn State College of Medicine, Hershey, PA; 8Division of Hematology, Mayo Clinic, Rochester, MN

Presented at the European Hematology Association (EHA) 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain

Disclosures for Talha Munir
Honoraria: Janssen, AbbVie, Gilead, Alexion, Novartis, Roche; Consultancy: MorphoSys, Sunesis.

2Introduction•Ibrutinib, a first-generation BTKi, is often associated with treatmentemergent side effects due to off-target binding•

Next-generation BTKis have been designed to improve selectivity andreduce toxicity1•Zanubrutinib (next-generation BTKi) and acalabrutinib (second-generationBTKi), have shown efficacy in clinical trials with better safety profiles thanibrutinib in B-cell malignancies2,3•

While direct comparison of zanubrutinib with acalabrutinib is lacking in theliterature, a recent meta-analysis of clinical trials by Hwang et al4 provided
a comprehensive comparison of AE profiles of zanubrutinib withacalabrutinib in B-cell malignancies

Adapted from Shadman M, et al. Lancet Haematol. 2023;10(1):e35-e45.5Objective: To evaluate the costs and quality of life (QoL) outcomes associated with the usageof zanubrutinib vs acalabrutinib based on their AE profiles as reported by Hwang et al.

AE, adverse event; BTKi; Bruton tyrosine kinase inhibitor; QoL, quality of life.
1. Estupiñán HY, et al. Front Cell Dev Biol. 2021;9:630942; 2. Brown JR, et al. N Engl J Med. 2023;388:319-332; 3. Byrd JC, et al. J Clin Oncol. 2021;39(31):3441-3452;
4. Hwang S, et al. Poster session presented at EHA June 8 - 15, 2023, Frankfurt, Germany; 5. Shadman M, et al. Lancet Haematol. 2023;10(1):e35-e45.

3

Meta-analysis of clinical trials by Hwang et al1•••

AEs of clinical interest reported by clinical trials of BTKis ibrutinib, acalabrutinib, and zanubrutinib in B-cell malignancies (selected by PubMed hematology/oncology congress
abstract searches) were analyzed in this meta-analysis
Specific AEs seen more commonly with acalabrutinib than zanubrutinib included: infections, atrial fibrillation, diarrhea, nausea/vomiting, headaches, cough, fatigue, and pyrexia
Specific AEs seen more commonly with zanubrutinib than acalabrutinib included: hematuria, neutropenia, and hypertension
All Grade AEs
Infection*
URI
Cellulitis*,aPneumonia
Hemorrhage
Contusion
Hematuria*
Neutropenia*
AnemiaThrombocytopenia
Neutropenic FeverHypertension*
Atrial Fibrillation*
Diarrhea*
Nausea*Vomiting*
Headache*Cough*
Fatigue*Pyrexia*
Arthralgia

Acalabrutinib
Incidence (%)
95% CI
64.08
53.93-75.58
18.24
14.46-23.13
5.34
2.66-8.89
9.72
7.51-12.71
35.81
29.59-43.22
14.13
10.85-18.37
4.33
2.52-7.09
16.55
13.15-20.73
15.13
11.82-19.22
10.62
8.15-13.85
1.58
0.88-2.93
6.56
4.81-8.82
4.93
3.45-7.00
32.98
27.69-39.11
17.35
13.74-21.74
9.95
7.60-12.92
30.96
24.63-38.87
19.29
15.44-24.21
19.20
15.49-23.74
14.68
11.60-18.65
12.72
9.77-16.72

Zanubrutinib
Incidence (%)
95% CI
32.22
26.81-38.38
18.97
15.09-23.81
36.82
28.99-47.44
9.29
7.10-12.12
40.44
33.65-48.39
14.77
11.53-18.97
10.55
7.91-14.07
27.88
22.54-34.51
12.81
10.02-16.35
13.20
10.42-16.711.33
0.73-2.16
8.96
6.90-11.60
2.38
1.58-3.38
15.85
12.98-19.67
10.21
7.88-13.13
6.84
4.78-9.51
9.51
7.18-12.54
13.04
10.27-16.53
10.83
8.47-13.76
8.27
6.17-10.96
11.23
8.72-14.41

Grade ≥3 AEs
Infection*
URI
Cellulitis*,aPneumonia
Hemorrhage
Contusion
Hematuria
Neutropenia*
Anemia*Thrombocytopenia
Neutropenic FeverHypertension*
Atrial Fibrillation
Diarrhea
NauseaVomiting
Headache
CoughFatiguePyrexia
Arthralgia

Acalabrutinib
Incidence (%)
95% CI
18.01
12.91-25.75
0.91
0.53-1.55
2.210.63-5.03
5.24
3.59-7.93
1.96
1.23-3.14
0.09
0.00-0.27
0.21
0.05-0.77
13.56
9.97-17.66
7.45
5.08-11.19
5.22
3.63-7.75
1.35
0.75-2.24
2.55
1.56-4.14
1.63
0.86-2.97
1.81
1.07-3.03
0.48
0.26-0.85
0.29
0.14-0.59
0.65
0.38-1.18
0.24
0.11-0.51
1.97
1.25-3.09
0.94
0.57-1.73
0.72
0.39-1.32

Zanubrutinib
Incidence (%)
95% CI
12.43
8.89-17.88
1.82
1.00-3.19
13.15
8.96-19.83
4.46
3.05-6.70
3.28
1.98-5.45
0.07
0.00-0.26
0.13
0.00-0.47
18.37
13.43-25.05
4.11
2.67-6.39
4.80
3.28-7.14
1.24
0.66-1.99
4.83
3.25-7.28
0.93
0.45-1.75
1.19
0.53-2.43
0.38
0.06-0.80
0.19
0.00-0.50
0.57
0.23-1.12
0.19
0.04-0.45
1.15
0.44-2.36
0.74
0.34-1.33
0.76
0.40-1.51*Statistically significant difference by relative risk. aReported as more common with zanubrutinib but excluded from the current economic analysis due to a data error as reported by the authors in Hwang et al. Cells inblue are AEs significantly higher for acalabrutinib. Cells in red are AEs significantly higher for zanubrutinib.

AE, adverse event; BTKi; Bruton tyrosine kinase inhibitor; CI, confidence interval; URI, upper respiratory infection.
1. Hwang S, et al. Poster session presented at EHA June 8 - 15, 2023, Frankfurt, Germany.

4Methods••

Total cost of managing AEs was estimated by summing the costs of Grade ≥3 and Grade 1/2 AEs
The QALY loss for each AE was calculated by multiplying the incidence rates with the disutility weights assigned to them and their durationCost of managing
Grade 1/2 AEs forzanubrutiniba

QALY loss due to
Grade 1/2 AEs forzanubrutinibc

Cost of managing
Grade 1/2 AEs foracalabrutiniba

QALY loss due to
Grade 1/2 AEs foracalabrutinibc++++

Cost of managing
Grade ≥3 AEs forzanubrutinibb=

QALY loss due to
Grade ≥3 AEs forzanubrutinibd=

Cost of managing
Grade ≥3 AEs foracalabrutinibb=

QALY loss due to
Grade ≥3 AEs foracalabrutinibd=

Cost of managing
an AE inzanubrutinib

Summing over allAEsTotal QALY loss dueto all AEs inzanubrutinib

QALY loss due to an
AE in zanubrutinib

Cost of managing
an AE inacalabrutinib

Total cost ofmanaging all AEs inzanubrutinib

Summing over all
AEsQALY loss due to an
AE in acalabrutinib

Cost= total cost of managing
all AEs in zanubrutinib total cost of managing all
AEs in acalabrutinib

Difference

Total cost ofmanaging all AEs inacalabrutinib

Total QALY loss due
to all AEs inacalabrutinib

QALY= total QALY loss due toall AEs in zanubrutinib total QALY loss due to all
AEs in acalabrutinib

aIncidence of Grade 1/2 AEs × unit cost of managing Grade 1/2 AEs. bIncidence of Grade ≥3 AEs × unit cost of managing Grade ≥3 AEs. cIncidence of Grade 1/2 AEs × disutility ofGrade 1/2 AEs × duration of Grade 1/2 AEs. dIncidence of Grade ≥3 AEs × disutility of Grade ≥3 AEs × duration of Grade ≥3 AEs.
AE, adverse event; QALY, quality-adjusted life year.

5Inputs and assumptions
Input item

Description

Incidence rates(IRs) for All Gradeand Grade ≥3 AEsof interest• Encompassed 20 different conditions including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache,arthralgia, diarrhea• Sourced from Hwang et al1• Excluded from this analysis due to a data error, as reported by the authors
Cellulitis data from• At their request, incorrect data concerning cellulitis has been removed, ensuring its incidence will be accurately reported inHwang et al1
the final publication
Disutility andaverage durationof AEs• Sourced from the published literature and previous NICE single technology appraisals (STAs)• Due to lack of evidence reporting disutility for Grade 1/2 AEs:o Disutility and average duration for Grade ≥3 AEs sourced from published literature or the NICE STAso Disutility for Grade 1/2 AEs assumed to be 30% less than that corresponding to severe AEs; assumption validated by clinical experts

Unit cost ofeach AE• Derived from National Schedule of NHS costs database2 (FY 2021-2022) using AE-specific Healthcare Resource Group (HRG)
codes, in consultation with clinical experts; all unit costs inflated to 2023 GBP

Model inputs fora few AEs*

• Could not be obtained from literature; a substitute value of another closely related AE was assumed in consultation with clinical experts*Hematuria, contusion, and neutropenic fever.
AE, adverse event; FY, fiscal year; GBP, British pound sterling; IR, incidence rate; NHS, National Health Service; NICE, National Institute for Health and Care Excellence.
1. Hwang S, et al. Poster session presented at EHA June 8 - 15, 2023, Frankfurt, Germany; 2. National Health Service (NHS). National Schedule of NHS Costs 2021/22. Available at:https://www.england.nhs.uk/publication/2021-22-national-cost-collection-data-publication/6

Analyses
Analysis typeDescriptionBase case• All AEs for a hypothetical cohort of 1,000 patients treated in clinical practice with zanubrutinib and acalabrutinib

Scenario• Grade ≥3 AEs, Grade 1/2 AEs, and AEs that were statistically significantly different in zanubrutinib and acalabrutinib arms (n=13)1

Sensitivity• Uncertainty around model parameters estimated in one-way sensitivity analysis (OWSA)• Consistency of results checked by probabilistic sensitivity analysis (PSA) with 1,000 iterations, assuming the appropriate
statistical distributions for parameters

AE, adverse event.
1. Hwang S, et al. Poster session presented at EHA June 8 - 15, 2023, Frankfurt, Germany.

7

Results: Base case analysis•In the base case, considering all AEs, treatment of a hypothetical cohort of 1,000 patients with zanubrutinib instead of acalabrutinib was associatedwith cost savings of £599K and 3.7 QALY savings

Cost Savings£2,930,429

13.1
Treated withacalabrutinib

AE, adverse event; QALY, quality-adjusted life year.

£599K

QALY Savings

3.7£2,331,858

9.4
Treated withzanubrutinib

8

Results: Scenario analyses••

Scenario analysis for Grade ≥3 AEs and Grade 1/2 AEs showed similar trends for cost savings and QALY savings
Scenario analysis limited to AEs significantly different between zanubrutinib and acalabrutinib yielded consistent results

Population
Hypothetical cohort(n=1,000) | Specific-grade AEs

Hypothetical cohort(n=1,000) | Significantly
different AEs

AE, adverse event; QALY, quality-adjusted life year.

AE GradeCost Savings(zanubrutinib vs acalabrutinib)

QALY Savings(zanubrutinib vs acalabrutinib)

Grade ≥3

£215,331

1.8

Grade 1/2

£383,2401.9All grades£627,638

3.9

Grade ≥3£219,749

1.8

Grade 1/2

£407,889

2.1

9

Results: Disaggregated by AE severity••

In the base case and scenario analyses, the relative contribution of Grade 1/2 AEs in cost savings was higher than Grade ≥3 AEs
In the base case and scenario analyses, QALY savings were similar among Grade ≥3 and Grade 1/2 AEs
QALY Savings(zanubrutinib vs acalabrutinib)

Cost Savings(zanubrutinib vs acalabrutinib)£750,000£500,000£250,000

0

£012

3

64%

36%

Base-case analysis(all AEs)

49%

51%

65%

35%

Scenario analysis(significant AEs)

46%

54%

Grade 1/2

AE, adverse event; QALY, quality-adjusted life year.

4Grade ≥310

Results: Sensitivity analyses••

OWSA results indicate:••

Infection IRs as most influential parameter affecting the cost savings
Disutility associated with headache and infection IRs in acalabrutinib as most influential parameters affecting QALYs

PSA results were consistent with the base case results, thus supporting the robustness of the analysis

OWSA: Results on Cost Savings for Zanubrutinib£431,345.3£581,345.3£731,345.3

OWSA: Results on QALY Savings for Zanubrutinib£881,345.3

2.9

Incidence rate – Grade ≥3 infection – acalabrutinib

Disutility – Grade ≥3 headache

Incidence rate – Grade ≥3 infection – zanubrutinib

Incidence rate – Grade 1/2 infection – acalabrutinib

Incidence rate – Grade ≥3 neutropenia – zanubrutinib

Incidence rate – Grade ≥3 infection – acalabrutinib

Incidence rate – Grade 1/2 infection – acalabrutinib

Disutility/duration decrement factor

Incidence rate – Grade ≥3 pneumonia – acalabrutinib

Disutility – Grade ≥3 infectionIncidence rate – Grade ≥3 neutropenia – acalabrutinib

Incidence rate – Grade 1/2 headache – acalabrutinib

Incidence rate – Grade 1/2 hemorrhage – zanubrutinib

Incidence rate – Grade ≥3 infection – zanubrutinib

Incidence rate – Grade 1/2 hemorrhage – acalabrutinib

Average duration – Grade ≥3 headache

Incidence rate – Grade >3 pneumonia – zanubrutinib

Incidence rate – Grade ≥3 neutropenia – zanubrutinib

Incidence rate – Grade ≥3 cough – zanubrutinib

Incidence rate – Grade ≥3 pneumonia – acalabrutinib

Cost savings – lower boundCost savings – upper bound

QALY savings – lower boundIR, incidence rate; OWSA, one-way sensitivity analysis; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year.

3.4

3.9

4.4

4.9

QALY savings – upper bound11

Limitations• Direct data such as disutility and duration of disutility of particular AEs* were not available• To mitigate this limitation, these assumptions were carefully considered, and the input of clinical experts was sought
to validate the assumptions and ensure they were reasonable within the context of current clinical practice• Economic and QoL benefits for zanubrutinib vs acalabrutinib demonstrated in this analysis wererestricted to the impact of AEs• Efficacy gains demonstrated for zanubrutinib vs acalabrutinib through indirect comparisons (eg, see Shadman et al. 20241)
were not considered*Hematuria, contusion, and neutropenic fever.
AE, adverse event; QoL, quality of life.
1. Shadman MS, et al. Poster session presented at ICHM Feb 29 - Mar 3, 2024; Miami, FL, USA.

12

Conclusions• If results derived from meta-analysis of clinical trial data (Hwang et al1) are assumed to begeneralizable to real-world patients, benefits to patients and payors would be substantial• A major strength of the study is the rigorous and robust analysis undertaken to evaluate

the safety profiles of zanubrutinib compared to acalabrutinib• This comprehensive economic analysis is grounded on an independent meta-analysis by Hwang et al1,
ensuring that our findings are based on a solid foundation of existing scientific evidence• This economic analysis demonstrated that zanubrutinib is cost-saving and associated withQoL benefits compared to acalabrutinib in terms of AE management in patients with B-cellmalignancies

AE, adverse event; QoL, quality of life.
1. Hwang S, et al. Poster session presented at EHA June 8 - 15, 2023; Frankfurt, Germany.

13

Acknowledgments• This study was sponsored by BeiGene, Ltd14