Zanubrutinib Prolongs PFS, Shows Trend Toward Improved OS in MAIC Analysis in CLL

Zanubrutinib (Brukinsa) demonstrated improved progression-free survival (PFS) and a trend for improved overall survival (OS) vs venetoclax (Venclexta) plus obinutuzumab (Gazyva) as first-line therapy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to findings from a matching-adjusted indirect comparison (MAIC) analysis of the phase 3 SEQUOIA (NCT03336333) and CLL14 (NCT02242942) trials.1

In findings presented at the 2025 SOHO Annual Meeting, zanubrutinib (n = 163) reduced the risk of disease progression or death by 44% vs venetoclax plus obinutuzumab (n = 216; HR, 0.66; 95% CI, 0.44-0.97; P = .0351); the Bruton tyrosine kinase inhibitor reduced the risk of death by 11% vs the combination (HR, 0.89; 95% CI, 0.55-1.46; P = .6468).

“This unanchored MAIC investigated the relative efficacy of zanubrutinib vs venetoclax plus obinutuzumab and demonstrated zanubrutinib had longer PFS and a trend for extended OS,” lead study author Talha Munir, MBChB, PhD, of Leeds Teaching Hospitals NHS Trust in the United Kingdom, and coauthors wrote in the poster.

Establishing the Need for the MAIC Analysis

In both the SEQUOIA and CLL14 trials, investigators demonstrated a significant improvement in PFS in the investigational arms relative to the control arms in the initial prespecified analyses.2,3

At a median follow-up of 61.2 months in SEQUOIA, the data continued to favor the use of zanubrutinib compared with bendamustine plus rituximab (Rituxan; BR), with a median PFS that was not reached vs 44.1 months, respectively (HR, 0.29; 1-sided P = .0001).2 In CLL14, with a median follow-up of 76.4 months, the PFS advantage also remained intact for venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab, with median values of 76.2 and 36.4 months, respectively (HR, 0.40; 95% CI, 0.31-0.52; P < .0001).3

Without a direct head-to-head comparison, investigators are left to tease out the appropriate clinical scenarios in which to use continuous with zanubrutinib vs fixed-duration therapy with venetoclax plus obinutuzumab.1 To better understand how both regimens stack up against each other, an unanchored MAIC was performed.

Performing the MAIC Analysis

The unanchored MAIC was conducted with 62.7 months of median follow-up data from SEQUOIA and 65.4 months of median follow-up data from CLL14. Individual characteristics of patients who had been received zanubrutinib in SEQUOIA were reweighted to match the key characteristics of those who received venetoclax plus obinutuzumab in CLL14. Matching adjustments for age, sex, ECOG performance status, CLL/SLL patient proportion, disease stage, IGHV mutation status, β2-microglobulin levels, creatinine clearance, B symptoms, and time from diagnosis were evaluated based on data availability and magnitude of imbalance between both populations.

After applying the matching adjustment to reflect the demographics of patients who received venetoclax and obinutuzumab in CLL14 (n = 216), the effective sample size for zanubrutinib in SEQUOIA went from 352 patients to 163.

To reduce the likelihood of confounding variables from the COVID-19 pandemic, additional analyses censoring for COVID-19–related deaths were performed. Sensitivity analyses were also conducted in model scenarios of different matching variables.

Baseline Characteristics Between Matched Zanubrutinib and Venetoclax/Obinutuzumab Arms

Within the zanubrutinib and venetoclax/obinutuzumab arms, the median age was 72.0 years; 33.3% of patients were 75 years or older, and most patients were male (67.6%). Genetics were normal in 23.8% of cases, and others had 17p deletions (8.1%), 11q deletions (17.1%), 12q translocations (17.1%), TP53 mutations (12.0%), or IGHV mutations (38.6%).

The median time from initial diagnosis was 31.0 months, and 48.0% of patients had B symptoms. Most patients had an ECOG performance status of 1 as opposed to 0 (45.8%) and 2 or higher vs 0 (13.0%). Binet stage was more commonly C vs A (43.5%) and B vs A (35.2%). With respect to laboratory parameters, β2-microglobulin levels rose above 3.5 mg/L in 59.4% of cases, with a median level of 3.9 mg/L. Creatinine clearance fell below 70 mL/min in 59.5% of cases, with a median level of 65.6 mL/min.

Additional Findings From the Censored and Sensitivity Analyses

Results from the primary base case–adjusted analysis were consistent with those from the COVID-19–adjusted analysis, with HRs of 0.58 (95% CI, 0.38-0.88; P = .0095) for PFS and 0.74 (95% CI, 0.43-1.25; P = .2587) for OS.

The efficacy of zanubrutinib vs venetoclax plus obinutuzumab was also compared in the IGHV-unmutated subgroup. After matching, the median PFS continued to favor the use of zanubrutinib in the effective sample size from SEQUOIA (n = 93) vs that from CLL14 (n = 121; HR, 0.63; 95% CI, 0.39-1.03; P = .0652). The same was true after adjusting for COVID-19–related scenarios (HR, 0.61; 95% CI, 0.37-0.99; P = .0475).

Sensitivity analyses evaluating the effect of using different pairs of matching factors yielded similar results. The effective sample sizes for zanubrutinib in the first, second, third, and fourth analyses were 154, 56, 116, and 108 patients, respectively. The HRs for PFS across the 4 sets were 0.67 (95% CI, 0.45-1.01; P = .0529), 0.73 (95% CI, 0.41-1.33; P = .3076), 0.62 (95% CI, 0.40-0.96; P = .0336), and 0.75 (95% CI, 0.49-1.15; P = .1884), respectively. The respective HRs for OS were 0.87 (95% CI, 0.52-1.46; P = .5947), 0.95 (95% CI, 0.47-1.91; P = .8759), 0.85 (95% CI, 0.49-1.48; P = .5579), and 1.03 (95% CI, 0.60-1.75; P = .9230).

In the face of COVID-19–adjusted scenarios, the HRs for PFS across the 4 sets were 0.59 (95% CI, 0.39-0.91; P = .0176), 0.61 (95% CI, 0.32-1.19; P = .1467), 0.52 (95% CI, 0.33-0.84; P = .0075), and 0.63 (95% CI, 0.39-0.99; P = .0456), respectively. The respective HRs for OS were 0.72 (95% CI, 0.41-1.26; P = .2481), 0.71 (95% CI, 0.31-1.64; P = .4232), 0.66 (95% CI, 0.35-1.23; P = .1924), and 0.78 (95% CI, 0.43-1.41; P = .4116).

“Results should be interpreted with considerations of MAIC model assumptions and limitations. Further studies are needed to confirm these findings,” study authors concluded.

Disclosures: Munir listed honoraria for BeOne Medicines Ltd, AstraZeneca, Sobi, Roche, Janssen, AbbVie, and Lilly; serving in a consultant role for AbbVie, BeOne Medicines Ltd, Sobi, Alexion, Novartis, Janssen, AstraZeneca, Lilly, and Roche; research grants from Janssen and AbbVie; travel, accommodations, or expenses from Alexion, BeOne Medicines Ltd, AbbVie, Janssen, and AstraZeneca; and serving on an advisory board for AbbVie, BeOne Medicines Ltd, AstraZeneca, and Janssen.

References

1. Munir T, Yang K, Mohseninejad L, et al. Efficacy of continuous Zanubrutinib vs fixed-duration venetoclax in combination with obinutuzumab in treatment-naive chronic lymphocytic leukemia: a matching-adjusted indirect comparison. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract CLL-109.
2. Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. 2025;43(7):780-787. doi:10.1200/JCO-24-02265
3. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924-1935. doi:10.1182/blood.2024024631