The objective of this analysis was to compare the efficacy of continuous zanubrutinib with treatments evaluated in the phase 3 CLL17 study and to assess whether conclusions drawn for ibrutinib could be generalized to zanubrutinib.

In the absence of head–to–head trials, an unanchored matching–adjusted indirect comparison was performed using individual patient data from SEQUOIA arms A and C (median follow-up, 58.0 months) and published aggregate data from the CLL17 study (median follow-up, 34.2 months). Feasibility assessment confirmed alignment in study design and eligibility criteria. However, owing to the limited follow-up for fixed duration regimens in CLL17 and the absence of COVID-19–adjusted overall survival (OS) data, continuous ibrutinib was the only methodologically feasible comparator. Zanubrutinib–treated patients were reweighted to match the CLL17 ibrutinib intent–to–treat population based on age, sex, Binet stage, ECOG performance status, presence of bulky disease, cancer type, and genomic risk factors. Sensitivity analyses using alternative matching factors were conducted. Investigator–assessed progression–free survival (PFS) and OS were evaluated. COVID–19–adjusted analyses were applied to SEQUOIA, as no COVID–19–related deaths were reported in the CLL17 ibrutinib arm.

After weighting, baseline characteristics were balanced between treatment groups, resulting in an effective sample size of 91 for zanubrutinib. COVID–19–adjusted investigator–assessed PFS significantly favored zanubrutinib compared with ibrutinib, with a hazard ratio of 0.23 (95% CI, 0.12–0.42). COVID–19–adjusted analyses for OS numerically favored zanubrutinib (HR, 0.70; 95% CI, 0.29-1.73). Results were consistent across multiple sensitivity analyses using alternative matching variables.