MAIC Shows Improved PFS With Zanubrutinib Over Ibrutinib in Treatment-Naive CLL

Findings from an unanchored matching-adjusted indirect comparison (MAIC) demonstrated that zanubrutinib (Brukinsa) monotherapy was associated with improved progression-free survival (PFS) and numerically favorable overall survival (OS) in patients with treatment-naive chronic lymphocytic leukemia (CLL).¹

Data presented at the 2026 EHA Congress showed that patients treated with zanubrutinib in the intention-to-treat (ITT) population (n = 352) from the phase 3 SEQUOIA trial (NCT03336333) experienced a 56% reduction in the risk of COVID-19–adjusted disease progression or death compared with patients treated with ibrutinib (Imbruvica; n = 301) in the phase 3 CLL17 trial (NCT04608318; HR, 0.44; 95% CI, 0.30-0.64; P < .0001). The PFS benefit improved following identification of the post-matching cohort of patients treated with zanubrutinib in SEQUOIA (n = 91; HR, 0.23; 95% CI, 0.12-0.42; P < .0001).

No statistical significance was observed in terms of OS outcomes, with similar effects observed between the SEQUOIA ITT population and the CLL17 group (HR, 1.17; 95% CI, 0.61-2.25; P = .6369). The population-adjusted estimate following matching showed a trend favoring the zanubrutinib group (HR, 0.70; 95% CI, 0.29-1.73; P = .4463).

“We had very good data coming from [the] phase 3 [CLL17] clinical trial looking at fixed-duration therapy [with venetoclax (Venclexta) plus obinutuzumab (Gazyva) or venetoclax plus ibrutinib], showing noninferiority [of the combinations] to the first-in-class BTK inhibitor ibrutinib,” lead study author Talha Munir, MBChB, PhD, said in an interview with OncLive^®. “[However], we can’t really say that with all the other BTK inhibitors. We don’t have phase 3 [data] comparing the second-generation BTK inhibitors [with] fixed-duration therapies, and I think we should always keep that in the back of our minds when choosing [a frontline] therapy. In my mind, the options that we need to give to our patients are still fixed-duration therapy, but also continuous therapy, because of the reasons that we are alluding to in this abstract.”

Munir is a consultant hematologist at Leeds Teaching Hospitals NHS Trust in the United Kingdom (UK) and the deputy chair of the UK National Cancer Research Institute CLL Study Group.

Data from the SEQUOIA and phase 3 ALPINE (NCT03734016) trials supported the January 2023 FDA approval of zanubrutinib for the treatment of patients with CLL or small lymphocytic lymphoma (SLL).² In March 2016, ibrutinib was approved by the FDA for patients with treatment-naive CLL/SLL, based on data form the phase 3 RESONATE-2 trial (NCT01722487).³

What was the rationale and design of the MAIC evaluating zanubrutinib in CLL?

Although data from the CLL17 trial showed noninferiority between ibrutinib and the venetoclax-based, fixed-duration regimens, the study authors sought to evaluate outcomes between ibrutinib monotherapy and zanubrutinib to determine if ibrutinib-based conclusions could be generalizable to zanubrutinib.¹

To conduct the MAIC, the investigators gathered data from patients treated with zanubrutinib in arms A and C of the SEQUOIA trial at a median follow-up of 58.0 months, along with aggregate data for patients treated with ibrutinib in CLL17 at a median follow-up of 34.2 months.

The SEQUOIA population, which included a higher-risk population of patients harboring 17p deletions (del[17p]) and other genomic risk factors, was then reweighted to match data from the CLL17 ITT population for factors such as age, sex, Binet stage, ECOG performance status, bulky disease status, cancer type, and genomic risk factors. With no deaths due to COVID-19 reported in the ibrutinib arm of CLL17, COVID-19–adjusted analyses were also used on the SEQUOIA population to improve comparability between the groups.

Investigator-assessed PFS and OS were evaluated via weighted Cox proportional hazard regression models.

Matching generated an effective sample size (ESS) population of 91 patients from SEQUOIA, and this group mirrored the CLL17 population in terms of median age (48.5 years), sex (male, 65.1%), ECOG performance status (0, 61.8%), CLL vs SLL (CLL, 100%), Binet stage B or C disease (74.8%), unmutated IGHV (56.8%), del(17p) (5.0%), del(11q) (21.6%), TP53 mutations (6.3%), and bulky disease (27.2%).

What was seen with COVID-19 adjustments in the zanubrutinib CLL MAIC?

Using an ESS of 62 patients from SEQUOIA following adjustments for COVID-19, the PFS benefit with zanubrutinib was retained vs ibrutinib (HR, 0.32; P = .0266). A numerical but not statistically significant OS trend was also maintained (HR, 0.69; P = .4940).

What were the limitations of the MAIC of ibrutinib in CLL?

The study authors noted that like any MAIC, there was a potential for bias due to the assumption that cross-trial difference can be entirely captured through variables selected for matching.

References

1. Munir T, Jurczak W, Mohseninejad L, et al. Zanubrutinib vs ibrutinib in treatment-naive chronic lymphocytic leukemia: implications for interpreting fixed-duration outcomes from CLL17. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract PS1718.
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed June 16, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. U.S. FDA approves Imbruvica (ibrutinib) for first-line treatment of chronic lymphocytic leukemia. News release. Johnson & Johnson. March 4, 2016. Accessed June 16, 2026. https://www.investor.jnj.com/investor-news/news-details/2016/U.S.-FDA-Approves-IMBRUVICA-ibrutinib-for-First-line-Treatment-of-Chronic-Lymphocytic-Leukemia-03-04-2016/default.aspx