Indirect Comparison of Efficacy of Zanubrutinib Versus Acalabrutinib inthe Treatment of Patients With Relapsed or Refractory Mantle Cell Lymphoma

P2058

Bijal Shah,1 Swetha Challagulla,2 Sheng Xu,3 Rhys Williams,2 Shijie Ren,4,5 Tushar Srivastava,4 Raju Gautam,4 Keri Yang2
1Moffitt Cancer Center, Tampa, FL, USA; 2BeiGene, San Mateo, CA, USA; 3BeiGene (Shanghai) Co, Ltd, Shanghai, China; 4ConnectHEOR Ltd, London, UK; 5SCHARR, University of Sheffield, Sheffield, UK
INTRODUCTIONR E S U LT S• Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin lymphoma,

Baseline Characteristics• Noticeable differences were observed in multiple baseline characteristics between• Zanubrutinib and acalabrutinib have demonstrated clinical benefits in separate

single-arm trials in patients with relapsed/refractory (R/R) MCL. However, theevidence on the comparative effectiveness of zanubrutinib and acalabrutinib islacking in the literature(95% CI: 0.35-0.94; P=.0272) (Figure 2, Figure 3)

Table 1. Summary of Key Baseline Patient Characteristics Identified as
Prognostic Variables and Effect Modifiers― Likewise, zanubrutinib had statistically significantly longer OS than acalabrutinib with anAcalabrutinib
ACE-LY-004(n=124)Age ≥65 years

64.5%

39.8%

Race: White

74.2%

24.4%

Gender: Male

79.8%

74.8%

• A targeted literature review was conducted in PubMed database and clinical trials

ECOG PS 1-2 (vs 0)

42.7%

35.8%

•sMIPI intermediate risk(vs low)

43.9%

37.4%

sMIPI high risk (vs low)

17.1%

15.4%

Bulky disease (LD ≥5 cm)

37.1%

38.8%

Ann Arbor stage III-IV75.0%

90.2%

Extranodal disease

72.6%••••••••

identifier (clinicaltrials.gov) to identify relevant clinical trial evidence
Data source for the efficacy of zanubrutinib was informed by the pooled individual
patient-level data (IPD) from 2 clinical trials: BGB-3111-206 (NCT03206970)3,4 andBGB-3111-AU-003 (NCT02343120)5The efficacy of acalabrutinib was informed by the published aggregated data of
the ACE-LY-004 trial (NCT02213926)6,7
A key difference among these trials was BGB-3111-206 had a Chinese population,
BGB-3111-AU-003 had a White population, whereas ACE-LY-004 was a global study
The efficacy outcomes of interest are progression-free survival (PFS), overall survival(OS), and overall response rate (ORR). The relative treatment effect were quantified
using hazard ratio (HR) for PFS and OS, and odds ratio (OR) for ORR
STC, an outcome regression-based approach to adjust for cross-trial differencesin patient characteristics, was used to estimate the relative efficacy of zanubrutinibvs acalabrutinib, following guidance by National Institute for Health and Care
Excellence Decision Support Unit Technical Support Document 18 (NICE DSUTSD18) (Figure 1)8The potential prognostic variables and effect modifiers were identified from thepreviously published ITCs in MCL and were further validated with clinical experts(Table 1)
In the base case analysis, all covariates for which the data were available in the
included trials of zanubrutinib and acalabrutinib were adjusted
Covariates included age, race, gender, Eastern Cooperative Oncology Group
Performance Status (ECOG PS) 1-2, simplified Mantle Cell Lymphoma InternationalPrognostic Index (sMIPI) intermediate and high risk, bulky disease, AnnArbor disease stage III-IV, extranodal disease, lactate dehydrogenase, priorlines of treatment, bone marrow involvement and prior autologous stem celltransplantation (SCT)
Sensitivity analyses were conducted by excluding the covariates (race and age) thatwere imbalanced largely across trials of zanubrutinib and acalabrutinib

Figure 1. Three-Step Approach for STC

STEP 1:Fitting a regression model (Cox regression for time-to-event outcome andlogistic regression for binary) to the IPD including all prognostic variables andeffect modifiers

STEP 2:
Predicting the outcome according to the comparator study population using
the mean baseline characteristics

STEP 3:
Deriving the estimate of ITC using the predicted estimate from step 2 and thereported estimate from the comparator study

26.6%

38.2%

Prior lines of treatment >2

22.6%

32.5%

Bone marrow involvement

50.8%

Prior autologous SCT

17.7%― For the ORR, the results of STC showed that odds of achieving ORR were higher forpatients treated with zanubrutinib than those treated with acalabrutinib (OR, 2.05 [95%
CI: 0.72-5.84]; P=.1798), but the difference did not reach a statistical significance (Figure 3)

zanubrutinib was associated with significantly greater PFS and OS vsacalabrutinib. Patients treated with zanubrutinib were also shown to beachieving numerically higher ORR than patients treated with acalabrutinib.
The study provides evidence to support the superiority of zanubrutinib overacalabrutinib in R/R MCL

Table 2. Sensitivity Analyses Results of STC Comparing Zanubrutinib vs
Acalabrutinib for Efficacy Outcomes• The proportion of patients with high LDH and >2 prior lines of treatment werefound to be significantly predictive of survival outcomes in the regression models

Figure 3. The Results of STC Comparing Zanubrutinib vs Acalabrutinib for
Efficacy Outcomes in the Base Case Analysis

PFSOS

HR

ORR

HR

0.57

OR

0.43

(95% CI: 0.35-0.94)
P=.027257.7%

Lactate dehydrogenase, high• The results of this population-adjusted ITC revealed that treatment with

HR of 0.43 (95% CI: 0.23-0.82; P=.0105) (Figure 2, Figure 3)

2.05(95% CI: 0.23-0.82)
P=.0105(95% CI: 0.72-5.84)
P=.1798

PFS
HR(95% CI, P value)

OSHR(95% CI, P value)

ORROR(95% CI, P value)

Sensitivity
analysis 1(base casewithout race)

0.62 (0.39-0.98,P=.0418)

0.42 (0.25-0.70,P=.0009)

1.48 (0.57-3.82,P=.4165)

Sensitivity
analysis 2(base casewithout age)

0.58 (0.35-0.97,P=.0388)

0.48 (0.25-0.94,P=.0335)

2.19 (0.73-6.52,P=.1606)

Sensitivity
AnalysesDISCUSSION• The strength of the present ITC study includes (i) the analysis was conducted per

standards documented in the NICE DSU TSD 18, with rigorous statistical methods
to provide reliable estimates; (ii) a large set of covariates, which in the opinion ofclinical experts could influence treatment outcomes, were adjusted in the analysis• Despite the thorough nature of the analysis, this study has certain limitations.

The study has restricted granularity and specificity due to reliance on the aggregateddata for comparator. The differences in designs, patient populations, or treatment
regimens across the studies being compared can introduce heterogeneity,
potentially affecting the validity of indirect comparisons

49.6%

Sensitivity Analysis• The sensitivity analyses, without adjusting for race and age, provided results

8.9%

consistent with base case analysis, demonstrating the robustness of the ITC
analysis using STC (Table 2)LD, longest diameter.

REFERENCES
Figure 2. Kaplan-Meier Curve for (A) PFS and (B) OSA

B+ Zanubrutinib,+ Zanubrutinib,+ Zanubrutinib,+ Acalabrutinib
STC STC + Zanubrutinib,
unadjusted
unadjusted + Acalabrutinib+++++++++++++++ +++++ +++++++0.75 0.75
++
1.00

+++++
1.00

++

0.50

0.50

0.25

0.25

0.00

1.00

++
++

++
++++++++++++++++++++++++++++ + ++ +++++++++++ +++ + +++++ ++++ + ++++++++++++++++++++++++ +++ + +++

06

612

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2430

3036

3642

4248

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4854

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6672

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Numberat riskat risk
Number−−−−−−

0.50

0.50

0.25

0.25

0.00

0.00
01.00++ ++ ++ ++++ + ++ ++++++ + ++++ + ++ +++ ++0.75 0.75+ +++++++1. Alu A, et al. J Hematol Oncol. 2022;15(1):138.
2. Rozkiewicz D, et al. Molecules. 2023;28(5):2400.
3. Song Y, et al. Clin Cancer Res. 2020;26(16):4216-4224.
4. Song Y, et al. Blood. 2022;139(21):3148-3158.
5. Tam CS, et al. Blood Adv. 2021;5(12):2577-2585.
6. Wang M, et al. Lancet. 2018;391(10121):659-667.
7. Le Gouill S, et al. Haematologica. 2024;109(1):343-350.
8. Phillippo DM, et al. NICE DSU Technical Support Document 18. Available fromhttp://www.nicedsu.org.uk+ Zanubrutinib,+ Zanubrutinib,+ Zanubrutinib,+ Acalabrutinib
STC STC + Zanubrutinib,
unadjusted
unadjusted + Acalabrutinib

OSMETHODS

PFS

R/R MCL, in the absence of head-to-head clinical trials, using population-adjusted
indirect treatment comparison (ITC) via simulated treatment comparison (STC)
approachBaseline Characteristics(Proportion of Patients)

PFS• To assess the comparative efficacy of zanubrutinib vs acalabrutinib in patients with

beneficial treatment effect in PFS, OS, and ORR (Figure 2, Figure 3)― Zanubrutinib had statistically significantly longer PFS than acalabrutinib with an HR of 0.57
Zanubrutinib
BGB-3111-206 +AU-003(n=123)OBJECTIVE• The results of STC showed that treatment with zanubrutinib was associated with athe zanubrutinib and acalabrutinib treatment cohorts• Zanubrutinib and acalabrutinib are second-generation Bruton tyrosine kinase

inhibitors (BTKis) with improved safety profiles compared with first-generation BTKi
ibrutinib in clinical trials1,2Base Case Analysis

OSwhich originates due to malignant transformation of B-cells in the mantle zone of thelymph follicle

C O N C LU S I O N+++++ ++++++++++++++++++++++++++++++++++++++ + +++++++++++++++ +++ + + +++++ +++ + + ++++++++++++ ++++++ ++++ ++++++++++++++++D I S C LO S U R E S

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612

1218

1824

2430

3036

3642

4248

4854

5460

6066

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72

Time, Time,monthsmonths

BS: Employment: Moffitt Cancer Center. Research Funding: Jazz Pharmaceuticals,Servier, Kite. Travel accommodations for Kite. Other relationships with DSMB,Pepromene Bio. SC, SX, RW, KY: Employment and may hold stock: BeiGene.
SR, TS, RG: Employment: ConnectHEOR.

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124
85

8575

7559

5952

5246

4637

3732

3229

2917

176

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124

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119

119
115

115
109

109
106

106
102

102
99

9996

9693

9393

930

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123
111

111
959589

8983

8376

7656

5613

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110

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101101
91

9185

8572

7267

6761

6156

5655

5541

417

70

0AC K N OW L E D G E M E N T S
This study was sponsored by BeiGene, Ltd. Editorial assistance was provided by SNELL
and was supported by BeiGene.

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