Comparative Efficacy of Bruton Tyrosine Kinase Inhibitors in the Treatment ofRelapsed/Refractory Chronic Lymphocytic Leukemia: A Network Meta-Analysis

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Mazyar Shadman,1 Jennifer R. Brown,2 Leyla Mohseninejad,3 Keri Yang,4 Heather Burnett,5 Binod Neupane,5 Rhys Williams,4 Nicole Lamanna,6 Susan M. O’Brien,7 Alessandra Tedeschi,8 Constantine S. Tam9
1Fred Hutchinson Cancer Center and University of Washington, Seattle, WA; 2Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 3BeiGene Netherlands B.V.,
Schiphol, Netherlands; 4BeiGene USA, Inc, San Mateo, CA; 5Evidera, Montreal, Canada; 6Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY; 7University of California, Irvine, CA; 8ASST Grande Ospedale
Metropolitano Niguarda, Milan, Italy; 9Alfred Hospital and Monash University, Melbourne, VIC, Australia
BACKGROUND• Next-generation Bruton tyrosine kinase inhibitors (BTKis) have led to changes in thetreatment algorithm for patients with high-risk relapsed/refractory chronic lymphocytic
leukemia (R/R CLL)1• Moreover, improved understanding of the CLL genome has facilitated the identificationof specific high-risk genetic features of disease, allowing a more personalized approach
to treatment2,3

Network Meta-Analysis• Fixed effect Bayesian NMA models were used to simultaneously synthesize the relativetreatment effects observed in each trial (i.e., hazard ratios [HRs]) and obtain estimates of
the relative treatment effects of all treatments in the network (Figure 1)(del[11q]), mutations in the TP53 gene, and unmutated immunoglobulin heavy-chain
variable region gene (IGHV) are likely to experience a more severe course of disease
and have an unfavorable prognosis with some treatment strategies4-6• Therefore, a network meta-analysis (NMA) was performed to estimate relative efficacy of• Given that data from ALPINE were collected during the COVID-19 pandemic, data wereFigure 1. Network Diagram

Feasibility Assessment• A systematic literature review was conducted in in July 20227 (updated January2023) to identify randomized controlled trials (RCTs) that reported overall survival(OS), progression-free survival (PFS), and response outcomes for approved andrecommended BTKi treatments (zanubrutinib, acalabrutinib, and/or ibrutinib) versus
any approved comparator for patients with R/R CLL• A total of three unique trials (reported across 22 publications) were considered for theALPINEELEVATE-RRASCEND• Assessment of differences in potential effect modifiers deemed important by clinicalexperts found the trials to be sufficiently similar with regards to most factors including
age, Eastern Cooperative Oncology Group (ECOG) status, bulky disease status, R/Rstatus, type of prior treatment (eg, fludarabine), and number of prior treatments (Table 1)• Key differences were identified in terms of del(17p), del(11q), and TP53 mutation statusacross the trials (Table 1)― The ELEVATE-RR trial included only patients with del(17p) or del(11q) mutations (46% del[17p]
and 64% del[11q]) while the proportion of patients with del(17p) and del(11q) mutations was
similar in the other 2 trials: 15-16% and 27%, respectively (Table 1)• Given these differences, NMAs were performed using available subgroup data reportedIbrutinib• High-risk populations were defined based on the pre-specified subgroups within eachtrial, including patients with del(17p) and/or TP53 mutations in ALPINE and ASCEND, anddel(17p)/del(11q) in ELEVATE-RR (as per the study inclusion criteria). Additional analyses
were also performed for subgroups based on del(17p) and TP53 mutation status alone,where data were available

Table 1. Study and Baseline Characteristics of Studies Included in NMA

BR/IRSample size

652

533

310

67 (35–90)

66 (28-89)

67 (32–90)% male68

71

67

ECOG (%)

0-1: 97
2: 30-1: 92
2: 80: 36
1: 51
2: 13

CR-INV

2.07 [0.50, 9.67], 84.4

1.84 [0.50, 7.20], 81.6

efficacious than all other treatments in the network when data from ALPINE wereadjusted for COVID-19, and all treatments except acalabrutinib when unadjusted data
were used• Available data used as inputs for the analyses are presented by high-risk population ofinterest in Table 2Response• In high-risk populations as defined by the individual trials, zanubrutinib versus ibrutinib
showed a more favorable investigator-assessed overall response rate (ORR-INV) anda trend favoring improvement in investigator-assessed complete response (CR-INV)(Table 3)― These findings were aligned with the results of the ALPINE trialNR50

42del(11q) (%)

2764

27del(17p) (%)

1546

16TP53 (%)

1540

24del(17p) and/or TP53

2351

28

Unmutated IGHV (%)

7386

74

Median number of priorlines (range)

1 (1-8)2 (1-12)2(1-10)No. prior lines (%)

1: 59
2: 24
3: 10

1-3: 88

8386

efficacious than ibrutinib and BR/IR, with trends in favor of zanubrutinib versus
acalabrutinibOverall Survival• The NMA results in terms of OS are presented in Figure 3• In high-risk populations as defined by the individual trials, although not statisticallysignificant, there were trends showing numerical benefit with zanubrutinib compared toibrutinib, acalabrutinib, and BR/IR, representing risk reductions of 41%, 28%, and 35%,respectively, with COVID-19 adjustment, and 31%, 16%, and 24% without• Findings were slightly less favorable for zanubrutinib when ALPINE data were not• Findings for response were consistent with or without ALPINE data adjusted for• OS analyses were not feasible across individual mutation types (del[17p] and TP53)

Table 2. Data Inputs Used for NMA

Figure 2. NMA Results for PFS Using COVID-19 Adjusted and Unadjusted Data from ALPINE Trial –Hazard Ratios and Probability Better for Zanubrutinib vs Comparators

and CR-INV; these findings were not statistically significant
COVID-19 (Table 3)

Del(17p)

High Riska

N
TrialComparators

ALPINE
COVIDadjusted

Zanubrutinib

75

Ibrutinib

ASCENDNN

1.89[0.53,6.75]

0.49[0.31,0.78]

0.59[0.31,1.12]

450.49[0.27,0.89]

50

0.49
[0.28,0.86]

75

Ref

Ref

Ref

Ref

50

Ref

45

Ref

75

2.64
[1.07,6.54]

1.67[0.52,5.37]

0.52[0.33,0.82]

0.69[0.38,1.24]

45

0.53
[0.30,0.94]

50

0.52
[0.30,0.90]

75

Ref

Ref

Ref

Ref

50

Ref

45

Ref

Acalabrutinib 268

1.61[1.01,2.56]

0.95[0.53,1.68]

0.90[0.70,1.16]

0.82[0.58,1.15]

124

1.00
[0.73,1.37]

100

0.95
[0.68,1.33]

Ibrutinib

265

Ref

Ref

Ref

Ref

121

Ref

112

Ref

Acalabrutinib

44NRNR

0.22[0.12,0.40]

0.90[0.45,1.79]

28

0.13
[0.06,0.29]

39

0.25
[0.14,0.45]

42

NR

NR

Ref

RefPFS-INV

HR[95% CI]

3.02[1.35,6.73]

BR/IR

80

HR [95% CI]

TP53mutationOS

Ibrutinib
ELEVATE-RR

OR [95% CI]

HR[95% CI]

21

Ref

PFS-INV

34

Ref

Trial-defined definition of high risk.
BR/IR, bendamustine + rituximab or idelalisib + rituximab; CI, confidence interval; CR, complete response; HR, hazard ratio; INV, investigatorassessed; NR, not reported; OR, odds ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Ref, reference for the HRaadjusted for COVID‑19‑related deaths

given a lack of reported subgroup data

ORR-INV CR-INV PFS-INV

ALPINE
Zanubrutinib
COVIDunadjusted

1: 48
2: 27
3: 13Ab, antibody; BR/IR, bendamustine + rituximab or idelalisib + rituximab; ECOG, Eastern Cooperative Oncology Group;
IGHV, immunoglobulin heavy-chain variable region gene; NMA, network meta-analysis.

• For those with TP53 mutations, zanubrutinib was found to be significantly more

• Findings versus acalabrutinib showed trends favoring zanubrutinib in terms of ORR-INV

46.5 (acalabrutinib)
45.3 (BR/IR)

Rai stage III–IV (%)

Prior anti-CD20 Ab (%)

1.69 [0.61, 4.97], 84.4

• Similarly, for patients with del(17p), zanubrutinib was found to be significantly more

RESULTS

Acalabrutinib vs BR/IR

39

Median age (range)

1.91 [0.75, 5.00], 91.7

― Findings were consistent when data from ALPINE were and were not adjusted for COVID-19-

BR/IR, bendamustine + rituximab or idelalisib + rituximab.

ASCENDMedian follow-up inmonths

40.9

ORR-INV

related deaths

based on mutation status

Zanubrutinib vs Ibrutinib Acalabrutinib vs Ibrutinib

1.73 [0.54, 6.23], 82.3

significantly more efficacious than ibrutinib, acalabrutinib, and bendamustine + rituximab
or idelalisib + rituximab (BR/IR), representing risk reductions of 51%, 45%, and 88%
respectively, with COVID-19 adjustment, and 48%, 42%, and 87% without

NMA: ALPINE, ELEVATE-RR, and ASCEND

Study arms

1.96 [0.55, 8.14], 84.9

with genetic high-risk features such as the presence of TP53 mutations and/or del(17p)

Figure 3. NMA Results for OS Using COVID-19 Adjusted and Unadjusted Data fromALPINE Trial – Hazard Ratios and Probability Better for Zanubrutinib vs Comparators in
High-Risk Patients
Overall Survival

Zanubrutinib vs.

Hazard Ratio (95% Crl)

Prob (zanubrutinib better)

Ibrutinib: adjusted

0.59 [0.31, 1.11]

94.8%

Ibrutinib: unadjusted

0.69 [0.38, 1.23]

89.2%

BR/IR: adjusted

0.65 [0.23, 1.73]

80.0%

BR/IR: unadjusted

0.76 [0.28, 1.98]

70.9%Acalabrutinib: adjusted

0.72 [0.35, 1.50]

81.5%

Acalabrutinib: unadjusted

0.84 [0.43, 1.68]

69.2%• In high-risk populations as defined by the individual trials, zanubrutinib was found to be

13

ELEVATE-RR

CR-INV

Progression-Free Survival• The NMA results in terms of PFS-INV are presented in Figure 2

underlying a valid NMA (homogeneity and transitivity of data from included studies)were met8-10

ALPINE

2.73 [1.11, 7.29], 89.7

Acalabrutinib• The feasibility of performing an NMA was assessed to ensure that the assumptions

Trial Name

3.09 [1.40, 7.26], 99.7

Analyses of response were not feasible versus BR/IR or across specific mutation types given a lack of reported subgroup data.
CR, complete response; CrI, credible interval; INV, investigator assessed; ORR, overall response rate.

Zanubrutinib

12ORR-INVaMETHODS

11

High Risk Without
COVID-19 Adjustment

Zanubrutinib vs acalabrutiniba

analyzed with and without adjustment for COVID-19-related deaths

approved and recommended BTKis used to treat high-risk R/R disease

High Risk With
COVID-19 Adjustment• This is the first NMA to compare the efficacy of BTKis in high-risk patients with R/R CLL• Findings suggest that zanubrutinib is likely to be the most efficacious BTKi for patients

Zanubrutinib vs ibrutinibaof odds ratios (ORs), each with the corresponding 95% credible intervals (CrI), whichreflect the range of true underlying effects with 95% probability. The probability thatzanubrutinib was better than each comparator treatment was also estimated for eachanalysis• There is a current lack of understanding around how BTKis compare in R/R CLL patientswith high-risk disease features

Odds ratio [95% CrI], Probability Better (%)• Analyses were performed in OpenBUGS (version 3.2.3)• Survival outcomes were analyzed in terms of HRs and response outcomes in terms• Patients with deletion of chromosome 17p (del[17p]), deletion of chromosome 11q

CON CLUSION S

Table 3. NMA Results for Response – Odds Ratios and Probability Better for
Zanubrutinib vs Comparators in High-Risk Patients

Progression-Free Survival
Zanubrutnib vs.
High Risk
Ibrutinib: Adjusted
Ibrutinib: Unadjusted
BR/IR: Adjusted
BR/IR: Unadjusted
Acalabrutinib: Adjusted
Acalabrutinib: Unadjusteddel(17p)
Ibrutinib: Adjusted
Ibrutinib: Unadjusted
BR/IR: Adjusted
BR/IR: Unadjusted
Acalabrutinib: Adjusted
Acalabrutinib: Unadjusted
TP53 mutation
Ibrutinib: Adjusted
Ibrutinib: Unadjusted
BR/IR: Adjusted
BR/IR: Unadjusted
Acalabrutinib: Adjusted
Acalabrutinib: Unadjusted

0.01

0.10

Favors zanubrutinib

110Hazard ratio (95% Crl)

Prob (zanubrutinib better)

0.49 [0.31, 0.78]
0.52 [0.33, 0.82]
0.12 [0.05, 0.26]
0.13 [0.06, 0.28]0.55 [0.32, 0.94]
058 [0.34, 0.99]

99.8%
99.7%
100%
100%
98.6%
97.8%

0.49 [0.27, 0.89]
0.53 [0.30, 0.94]
0.06 [0.02, 0.18]
0.07 [0.02, 0.19]
0.49 [0.25, 0.98]
0.53 [0.28, 1.03]

98.9%
98.4%
100%
100%
97.8%
97.0%

0.49 [0.28, 0.85]
0.52 [0.30, 0.90]
0.13 [0.05, 0.34]
0.14 [0.06, 0.33]
0.52 [0027, 1.00]
0.55 [0.29, 1.05]

99.4%
98.9%
100%
100%
97.4%
96.6%

100

Favors comparator

BR/IR, bendamustine + rituximab or idelalisib + rituximab; CrI, credible interval; Prob, probability better.

0.01

0.10

Favors zanubrutinib

110100Favors comparator

BR/IR, bendamustine + rituximab or idelalisib + rituximab; CrI, credible interval; Prob, probability better.

LIMITATIONS• The structure of the network must be considered in the context of our findings,

specifically for comparisons of zanubrutinib versus BR/IR, which relies on indirect
evidence (via ibrutinib), thereby decreasing the certainty of relative effect estimates• The size of some of the subgroups used for NMA were limited, particularly those fromASCEND and the separate del(17p) and TP53 mutated groups from ALPINE• The definition of high-risk varied between the studies included in this NMA. The

ELEVATE-RR trial exclusively enrolled patients with del(17p)/del(11q), while ALPINE andASCEND did not limit enrollment to this population, nor did they report subgroup resultsfor patients with del(11q)― Despite this limitation, findings of analyses for PFS based on del(17p) and TP53 mutation statusseparately, were consistent with the base case

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DISCLOSURES
MS: Consultant: AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, BMS,
MorphoSys/Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics,
Fate Therapeutics, Janssen and MEI Pharma. Research funding: Mustang Bio, BMS,
Pharmacyclics, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Genmab,MorphoSys/Incyte, Vincerx. JRB: Consultant: Abbvie, Acerta/Astra-Zeneca, Alloplex
Biotherapeutics, BeiGene, Bristol-Myers Squibb, Galapagos NV, Genentech/Roche,
Grifols Worldwide Operations, InnoCare Pharma Inc, iOnctura, Kite Pharma, Loxo/Lilly,
Merck, Numab Therapeutics, Pfizer, Pharmacyclics. Research funding: BeiGene, Gilead,iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics. Serves on the Data Safety Monitoring
Board for Grifols Therapeutics. LM and KY: Employment and may hold stock: BeiGene.
HB and BN: Employment: Evidera. NL: SAB/Consultant/Honoraria: AbbVie, Adaptive
Biosciences, Allogene Therapeutics, AstraZeneca, BeiGene, Genentech, Janssen, LOXO/Eli Lilly, Pharmacyclics. Received honoraria from: Aptitude Health, BioAscend, Clinical CareOptions, Curio, DAVA Oncology, OncLive, PER, Peerview, Targeted Oncology. Institutional
Research funding: AbbVie, AstraZeneca, BeiGene, Genentech, Genmab, LOXO/Eli Lilly,MingSight, Octapharma, Oncternal.
Presented at EHA 2024; June 13-16, 2024; Madrid, Spain/Virtual Conference