Efficacy and Safety of Zanubrutinib Versus Venetoclax+Ibrutinib in Treatment-NaïveChronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison

P702

Talha Munir,1 Leyla Mohseninejad,2 Pal Rakonczai,3 Sheng Xu,4 Keri Yang,5 Aileen Cohen,5 Remus Vezan,5 Nicolas Martinez-Calle6
1Leeds Teaching Hospitals NHS Trust, Leeds, UK; 2BeiGene Netherlands B.V., Schiphol, The Netherlands; 3Evidera, Budapest, Hungary; 4BeiGene (Shanghai) Co, Ltd, Shanghai, China;
5BeiGene USA, Inc, San Mateo, CA, USA; 6Nottingham University Hospital, Nottingham, UK
RE S ULTS
1,2for the treatment of chronic lymphocytic leukemia (CLL). The phase 3 SEQUOIA study evaluatedthe efficacy and safety of zanubrutinib in treatment-naïve (TN) patients with CLL with no del(17p)
mutations (Arm A, zanubrutinib; Arm B, bendamustine+rituximab), and with del(17p) mutations (Arm C,zanubrutinib)• The combination of fixed-duration B-cell lymphoma-2 inhibitor (BCL2i) venetoclax plus the BTKi
ibrutinib (V+I) was approved by the European Medicine Agency for the treatment of TN CLL. V+I hasbeen evaluated in the phase 3 GLOW study3 including older patients and/or those with comorbidities
and excluding the del(17p)/TP53 population, and in the phase 2 CAPTIVATE study including younger/
fitter patients and no restrictions on del(17p) and TP534

Population Adjustment

PFS-INV• A matching model adjusting for all commonly available characteristics, except CIRS, including age, sex,

• Both naïve and population-adjusted comparison of PFS-INV for zanubrutinib in SEQUOIA (Arm A) vs V+I

geographic region, ECOG PS, cancer type, CLL stage, various genomic mutation status, bulky disease,beta2-microglobulin, time from diagnosis, and creatinine clearance level in the GLOW population wassuccessfully fitted with ESS=152 (63% of Arm A in SEQUOIA) (Table 1). CIRS was excluded from thematching due to the large imbalance between SEQUOIA (27%) and GLOW (70%) populations, which
would lead to a drastic drop in ESS. Adding CIRS was explored as part of the sensitivity analysis andresults are presented in the sensitivity analysis section

V+Iin GLOW

was conducted to evaluate the relative efficacy and safety of the 2 treatments

n=106

Postmatching,
ESS=152✓

717071Male, %✓55.7%

63.9%

55.7%

Geographic region,
North America, or Europe, %✓86.8%

86.3%

ECOG PS = 0, %✓33.0%SLL (vs CLL), %✓Binet stage C, %MAICs were conducted–Population CharacteristicsO BJE C TI V E• The objective of this study was to conduct a matching-adjusted indirect comparison (MAIC) between
zanubrutinib and V+I, and reduce potential bias due to differences in study populations

M E TH O D S• Individual patient-level data (IPD) from SEQUOIA was matched against the aggregate data from GLOWand CAPTIVATE• Due to the lack of common control arms linking SEQUOIA with GLOW or CAPTIVATE, 2 unanchoredIn MAIC-1, the zanubrutinib population from Cohort 1 in SEQUOIA (Arm A) was reweighted tomatch the key characteristics of the V+I population in GLOW (Figure 1)

Figure 1. MAIC-1

Cohort 1, Arm A,
SEQUOIA (n=241)

Individual patient-level data
Follow-up, median: 43.7 months
Treatment exposure, median: 43.3 months†

V+I fixed-duration,GLOW (n=106)

Published aggregate data
Follow-up, median: 27.7 months*
Treatment exposure, median: 13.8 months† One patient who did not receive zanubrutinib treatment was excluded in the safety analysis.
* Median follow-up is not reported separately for V+I in GLOW, but only for pooled arms.

–Median age, years

Zanubrutinib
in SEQUOIA Cohort 1
Prematching,
n=241

MAIC-1

Includedin Matching

In MAIC-2, the pooled zanubrutinib population from Cohort 1 and 2 in SEQUOIA (Arm A+C) wasreweighted to match the key characteristics of the V+I population in CAPTIVATE (Figure 2)

Figure 2. MAIC-2

Arm A+C
SEQUOIA (n=352)

Individual patient-level data
Follow-up, median: 45 months
Treatment exposure, median: 44.1 months†

V+I fixed-duration,
CAPTIVATE (n=159)

Published aggregate data
Follow-up, median: 49.8 months
Treatment exposure, median: 13.8 months

or prognostic factors including age, sex, geographic region, Eastern Cooperative Oncology Group
Performance Status (ECOG PS), cancer type, CLL stage, genomic mutation status, bulky disease,beta2-microglobulin, complex karyotype, time from diagnosis, Cumulative Illness Rating Score (CIRS),
and creatinine clearance were considered based on availability across the studies, clinical relevance,and magnitude of imbalance across study populations• Adjusting for all commonly available characteristics resulted in insufficiently low effective sample
size (ESS); several simpler matching models were explored to find the most optimal matches. Afterthe matching model was identified, balancing weights were derived for zanubrutinib patients in theSEQUOIA study• Pseudo IPD for investigator-assessed progression-free survival (PFS-INV) in the V+I arms werereconstructed from the digitized Kaplan-Meier (KM) curves reported in the GLOW and CAPTIVATE
publications using the algorithm by Guyot et al5• Weighted Cox proportional hazard regression was used to derive relative treatment effect estimatesfor PFS-INV• Given that matching variables mainly impact efficacy and not safety, the primary safety comparison
did not apply weights used in the efficacy comparison; naïve comparison using logistic regression
was carried out as the primary approach. Weighted logistic regression using weights from the efficacycomparison was carried out as part of the sensitivity analysis

overlap in population characteristics across SEQUOIA and the V+I studies, both naïve and populationadjusted relative treatment effect estimates had large uncertainty. Therefore, no statistically significant
differences in PFS could be demonstrated for zanubrutinib vs V+I• As shown in the comparison of postmatching zanubrutinib vs V+I (CAPTIVATE) (Figure 4), the PFS-

the adjusted estimates showed a potential trend for treatment benefit in favor of zanubrutinib vs V+I• Zanubrutinib showed a significantly better safety profile vs V+I, despite longer treatment exposure(median 43-44 months vs 13.8 months in both V+I studies)• The observed safety differences between zanubrutinib and V+I suggest considerable impact onpatients’ quality of life, which should be considered at the time of treatment decision-making in TN CLL• Comparing against CAPTIVATE, including adjustment for bulky disease instead of maximum age inthe matching model (Table 2), resulted in ESS=55 and HR=0.83 (95% CI: 0.43-1.61, P=.5869). Similarly,including adjustment for complex karyotype resulted in ESS=32 and HR=0.78 (95% CI: 0.33-1.87, P=.5834)– To increase ESS, a simplified model adjusting for limited set of population characteristics was
further explored. This exploratory model included adjustments only for IGHV, del(17p) and del(11q)
mutation status, CLL stage, and age, and resulted in a considerably higher ESS of 91 and HR=0.66(95% CI: 0.34-1.26, P=.2047)

Safety Outcomes

86.8%

45.6%

33.0%–• Notably, zanubrutinib usage led to significantly lower proportions of diarrhea, neutropenia, nausea,

9.4%

8.3%

9.4%

✓40.6%

29.0%

40.6%

Mutated IGHV, %✓32.9%

47.2%

32.9%

Del(17p), %

✓0.0%

0.8%

0.0%

Del(11q), %

✓

18.9%

17.8%

18.9%

TP53 mutation, %

✓6.6%

6.5%

6.6%

Bulky disease, LD in cm, ≥5, %✓39.0%

28.6%

39.0%

Beta2-microglobulin >3.5 mg/L, %✓69.8%

57.3%

69.8%

Median time from diagnosis, months

✓

35.8

3136

Median creatinine clearance, mL/min

✓

66.5

7166

CIRS >6, %x69.8%

27.1%

30.9%

CIRS, Cumulative Illness Rating Score; IGHV, immunoglobulin heavy-chain variable; LD, longest diameter; SLL, small lymphocytic leukemia.

• Compared to SEQUOIA, the CAPTIVATE population was significantly younger (median age, SEQUOIA:

Longer follow-up would be required to make a more informed conclusion, as well as adjustment forthe misalignment in the assessment schedules between the 2 studies

V+I inCAPTIVATE

Figure 3. MAIC-1 PFS-INV

n=159

PostmatchingESS=51

✓60

7060

Maximum age, years✓718771

Male, %✓67.0%66.2%

67.0%

ECOG PS = 0, %✓69.2%

43.8%

69.2%

SLL (vs CLL), %

✓

8.0%

8.8%

8.0%

Rai stage III-IV,† %

✓

28.0%

31.0%

28.0%

Mutated IGHV, %

✓

42.6%

43.8%

42.6%

Del(17p), %

✓

12.7%

31.8%

12.7%

Del(11q)*, %

✓

17.7%

11.6%

17.7%

Trisomy 12*, %

✓

14.6%

12.5%

14.6%

Median age, years

Population Characteristics

Normal*, %

✓

20.9%

15.9%

20.9%

Del(13q)*, %

✓

34.1%

28.2%

34.1%

TP53 mutation, %✓10.3%

18.2%

10.3%

Bulky disease, LD in cm, ≥5, %✓30.2%

32.1%

25.6%

Complex karyotype ≥3abnormalities, %x23.3%

22.3%

16.0%

† Since Rai stage was not reported in SEQUOIA, Binet C was used as a proxy for Rai III-IV. * As per hierarchical classification.
LD, longest diameter; V+I, venetoclax + ibrutinib.

anemia, atrial fibrillation, decreased appetite, and arthralgia

Zanubrutinib ITT

Zanubrutinib postmatchingcomparison for the safety comparison demonstrated results that were consistent with the unadjusted
safety comparison (see appendix in QR code)

V+I

Figure 5. Adverse Events of any Grade or Grade 3+ by Preferred Term with a P value <.2 in the Naïve
Safety Comparison

1.00

Adverse Events
Diarrhea, any grade

0.75

Diarrhea, grade 3+
Neutropenia*, any grade
Neutropenia*, grade 3+

0.50

Nausea, any grade
Anemia, any grade
UTI, any grade
Edema peripheral, any grade
Atrial fibrillation, any grade
Atrial fibrillation, grade 3+
Decreased appetite, any grade
Thrombocytopenia, any grade
Thrombocytopenia, grade 3+
Arthralgia, any grade
Epistaxis, any grade
Cough, any grade
Hyponatremia, grade 3+0.25
Zanubrutinib (SEQUOIA, Arm A) vs V+I (GLOW)
Naïve comparison: HR=0.71 (95% CI: 0.39-1.28), P=.2578
Population-adjusted comparison: HR=0.84 (95% CI: 0.45-1.59), P=.5977
0.00
06

1218

24

30

36

4248

Time, months
Number at risk
241
152
106

234
147
98

228
142
91

219
138
89

208
131
72

Comparator
Study
GLOW
CAPTIVATEGLOWGLOWCAPTIVATEGLOWCAPTIVATEGLOWCAPTIVATE
GLOW
GLOW
GLOW
GLOW
GLOW
GLOW
GLOW
GLOW
CAPTIVATE
GLOW
GLOW
GLOW

V+I
(Events/N)
54/10699/15911/10644/10666/159
37/10652/15928/10668/15919/106
17/106
16/106
15/106
7/106
14/106
12/106
6/106
53/15912/1069/106
6/106

Zanubrutinib(Events/N)
41/24063/351
4/240
32/24045/351
24/24036/351
31/24051/351
16/24024/24023/24010/2402/240
7/240
12/2404/240
63/351
13/24035/2405/240Naïve OR(95% CI)
0.20 (0.12–0.33)
0.13 (0.09–0.20)
0.15 (0.05–0.47)
0.22 (0.13–0.37)
0.21 (0.13–0.32)
0.21 (0.12–0.37)
0.24 (0.15–0.38)
0.41 (0.23–0.73)
0.23 (0.15–0.35)
0.33 (0.16–0.67)
0.58 (0.30–1.14)
0.60 (0.30–1.18)
0.26 (0.11–0.61)
0.12 (0.02–0.58)
0.20 (0.08–0.50)
0.41 (0.18–0.95)
0.28 (0.08–1.02)
0.44 (0.29–0.67)
0.45 (0.20–1.02)
1.84 (0.85–3.98)
0.35 (0.11–1.19)
0201
123
21190
116
093
59
0

0.5

11.5

P Value<.001<.001.001
<.001
<.001
<.001
<.001.003<.001.002
.112
.138
.002
.009
.001
.038
.054
<.001
.056
.121.093

2Favors zanubrutinib Favors V+l2314
0* In GLOW neutropenia indicates neutropenia and neutrophil count decreased.
UTI, urinary tract infection; V+I, venetoclax + ibrutinib.

Zanubrutinib
in SEQUOIA Cohort 1 and 2Prematching
n=352

Includedin Matchingwith regards to multiple AEs (Figure 5)• Sensitivity analyses exploring the impact of using the same matching factors from the efficacy• Further adjustment for bulky disease and complex karyotype was not feasible due to their impact on the ESS• Baseline characteristics related to beta2-microglobulin and geographic region were not available inTable 2. Matching and Baseline Characteristics Between CAPTIVATE and SEQUOIA Cohort 1 and 2• Significantly lower incidence was indicated for zanubrutinib vs V+I in both GLOW and CAPTIVATE studies

Sensitivity Analysis (safety)

70 years; CAPTIVATE: 60 years) and had significantly better heath state (proportion of patients withlowest ECOG PS was 69.2% vs 43.8%) (Table 2). Therefore, a matching model adjusting for age, sex,
ECOG PS, cancer type, CLL stage, and various genomic mutation status was fitted with rather low
ESS=51, only 14.5% of the sample size of Arm A+C population in SEQUOIA† One patient who did not receive zanubrutinib treatment was excluded in the safety analysis.

• Adjustments for all key population characteristics identified as potential treatment effect modifierswith HR=1.00 (P=.9874) indicated that treatment effects were similar, the population-adjusted estimate
HR=0.78 (P=.5099) indicated a trend for potential treatment benefit in favor of zanubrutinib vs V+I(Figure 4). No statistical significance was observed• No statistically significant differences in PFS could be demonstrated for zanubrutinib vs V+I. However,

INV KM curves overlap over the first 9 months, then the V+I curve is above the zanubrutinib curve up
to 28 months when the curves start overlapping again. In addition, there is notable declination in theV+I curve at around 40 months that could be partly explained by the fact V+I is fixed-duration, while
zanubrutinib is a continuous treatment with no declination related to any specific timepoint during theobserved period. The difference observed at the tail of the 2 curves leads to a HR estimate indicatinga numerical benefit in favor of zanubrutinib

CAPTIVATE for matching
MAIC-2• While in the naïve comparison of PFS-INV for zanubrutinib in SEQUOIA (Arm A+C) vs V+I in CAPTIVATE• Due to the relatively low sample sizes in V+I arms in GLOW and CAPTIVATE and the relatively lowTable 1. Baseline Characteristics of Zanubrutinib Arm in SEQUOIA and V+I Arm in GLOW

• As no head-to-head clinical studies comparing zanubrutinib versus V+I exist, an indirect comparisonin GLOW indicated a trend for potential treatment benefit in favor of zanubrutinib with HR=0.71 (P=.2578)
and HR=0.84 (P=.5977), respectively (Figure 3), however, no statistical significance was observed

Progression-free survival by INV• Zanubrutinib is a highly effective next-generation Bruton tyrosine kinase inhibitor (BTKi) approved

C ONC LU S IONS

LI M I TAT I ONS• In any MAIC, there is a potential for bias resulting from the strong assumption that cross-trial differences

Figure 4. MAIC-2 PFS-INV
Zanubrutinib ITT

Zanubrutinib postmatching

can be entirely explained by variables selected for matching

V+I• Overall survival was not included in the MAIC analysis due to immaturity of data
• An important limitation of the safety comparison is that CAPTIVATE reported AEs only if they exceeded

1.00

30% in all grade or 5% in grade 3+. Therefore, the comparison of AEs with 10%-30% incidence inall grade was not possible unless their grade 3+ incidence exceeded 5%
Progression-free survival by INV

IN T R O D U CT I O N

0.75

RE F E RE NC E S
1. Tam CS, et al. Lancet Oncol. 2022;23:1031-1043.
2. Munir T, et al. Poster session presented at: EHA 2023; 2023 June 8-11; Frankfurt, Germany.
3. ClinicalTrials.gov identifier: NCT03462719. Updated 2023-03-28. https://clinicaltrials.gov/study/NCT03462719
4. ClinicalTrials.gov identifier: NCT02910583. Updated 2023-04-03. https://clinicaltrials.gov/study/NCT02910583
5. Guyot P, et al. BMC Med Res Methodol. 2012;12:9.

0.50

0.25

D I S C LOS URE S

Zanubrutinib (SEQUOIA, Arm A+C) vs V+I (CAPTIVATE)Naïve comparison: HR=1.00 (95% CI: 0.65-1.52), P=.9874
Population-adjusted comparison: HR=0.78 (95% CI: 0.38-1.62), P=.5099

TM: Research Funding: Janssen, AbbVie; Honoraria: AbbVie, Janssen,AstraZeneca, Eli Lilly, Novartis, Roche, Sobi, Alexion, BeiGene; Advisory
Committees: AbbVie, Janssen, AstraZeneca, Eli Lilly, Novartis, Roche, Sobi,Alexion, BeiGene. LM, SX, KY, AC, RV: Employment and may hold stock
options: Beigene. PR: Employment: Evidera. NMC: Honoraria: BeiGene, AbbVie,AstraZeneca; Consulting: BeiGene, AbbVie, Takeda; Travel support: AbbVie

0.00
0612182430364248291
42132279
38130168
23115

496111

Time, months
Number at risk
35251159341
50153333
481523184614430345143

2AC K NOWLE D G E M E NTSThis study was sponsored by BeiGene, Ltd. Editorial assistance was provided byEvidera, and supported by BeiGene.

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