Efficacy and Safety of Zanubrutinib vs. Venetoclax+Ibrutinib in the Treatment-naïve (TN) Chronic
Lymphocytic Leukemia (CLL): A Matching-Adjusted Indirect Comparison (MAIC)
Talha Munir*1, Leyla Mohseninejad2, Pal Rakonczai3, Sheng Xu4, Keri Yang5, Aileen Cohen5, Remus
Vezan5, Nicolas Martinez-Calle6
1Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, 2BeiGene Netherlands B.V., Schiphol, TheNetherlands, 3Evidera, Budapest, Hungary, 4BeiGene (Shanghai) Co., Ltd., Shanghai, China, 5BeiGene
USA, Inc., San Mateo, CA, United States of America, 6Nottingham University Hospital, Nottingham,United Kingdom

Background: Zanubrutinib (zanu) is a highly effective Bruton tyrosine kinase inhibitor (BTKi) approved
for the treatment of CLL. The phase 3 SEQUOIA trial (NCT03336333) evaluated the efficacy and safety ofzanu in TN CLL patients with no del17p mutations (arm A, zanu; arm B, bendamustine+ rituximab), andwith del17p mutations (arm C, zanu). The combination of fixed duration BCL-2 inhibitor venetoclax (V)plus the BTKi ibrutinib (I) was approved by the European Medicine Agency (EMA) for the treatment ofTN CLL. V+I has been evaluated in GLOW (NCT03462719) including older/comorbid patients andexcluding the del17p/TP53 population and in CAPTIVATE (NCT02910583) including younger/fitterpatients and no restrictions on del17p and TP53. As no head-to-head clinical study comparing zanu vs.
V+I exists, an indirect comparison is required to evaluate the efficacy and safety of the two treatments.
Aim: To conduct a population adjusted indirect comparison between zanu and V+I and reduce potentialbias due to differences in study populations.
Methods: Since SEQUOIA and the V+I studies cannot be linked through a common control arm, twounanchored MAICs were conducted, matching individual patient data (IPD) from arm A of SEQUOIA vs.
the V+I arm of GLOW, and pooled arm A+C of SEQUOIA vs. the V+I arm of CAPTIVATE. Adjustments forage, sex, geographic region, CLL stage, cancer type, cytogenetic mutations, complex karyotype, ECOG,
bulky disease, time from diagnosis, beta2-microglobulin, and creatinine clearance were consideredbased on availability and magnitude of imbalance between populations. Weighted Cox regression wasused to derive relative treatment effect estimates. 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 was carried out as the primary approach.
Results: For PFS, unadjusted comparison between zanu in SEQUOIA arm A (n=241) and V+I in GLOW
(n=106) indicated potential treatment benefit in favor of zanu (HR=0.71 [95%CI: 0.39-1.28, p=0.2578]).
After matching, the two treatments were similar (HR=0.84 [95%CI: 0.45-1.59, p=0.5977]). The
unadjusted comparison between zanu in SEQUOIA arm A+C (n=352) and V+I in CAPTIVATE (n=159) also
indicated a similar treatment effect for zanu and V+I (HR=1.00 [95%CI: 0.65-1.52, p=0.9874]). After
matching, the HR=0.78 (95%CI: 0.38-1.62, p=0.5099) showed a potential benefit for zanu. For safety,
significantly lower incidence was indicated for zanu vs. V+I in both GLOW and CAPTIVATE with regards tomultiple adverse events (AEs) (figure). Sensitivity analyses exploring the impact of using different sets ofmatching factors in the efficacy comparisons and population matching in safety comparisons showed
consistent results.
Summary/Conclusion: Due to low sample size of V+I studies and the high variability in population
characteristics, the relative treatment effect estimates had a wider probability range. However, theEHA 2024

adjusted estimates of the relative treatment effect suggest a potential trend for PFS benefit in favor ofzanu vs. V+I. Comparison of AE incidence rates across SEQUOIA and V+I studies identified a significantly
better safety profile for zanu vs. V+I, despite longer treatment exposure for zanu (median 44 months)
compared to V+I (median 13.8 months in both trials) and no adjustment for differences in treatment
exposure were made in the safety comparisons. The observed safety differences between zanu and V+I
suggest considerable impact on patients quality of life, that should be weighted at the time of treatment
decision-making in TN CLL.

EHA 2024

Figure. Forest plot of AEs of any grade or grade 3+ with a p-value <0.2 in the safety comparison against
the GLOW and CAPTIVATE studies.

*Comparison against GLOW includes “neutrophil count decreased”.
Abbreviations: AE, adverse event; CI, confidence interval; OR, odds ratio; UTI, urinary tract infection.

EHA 2024