Outcome comparison of once versus twice daily dosing of zanubrutinib.

7049 Background: Zanubrutinib, a Bruton tyrosine kinase inhibitor (BTKi), approved as frontline treatment in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), can be dosed as 320mg once daily (QD) or 160mg twice daily (BID). In phase I trials 160mg BID and 320mg QD achieved comparable BTK occupancy in peripheral blood. While most clinical trials utilized BID dosing, there is limited data evaluating outcomes between regimens. Thus, we performed a retrospective study comparing outcomes of QD vs BID dosing of zanubrutinib in frontline CLL/SLL patients (pts). Methods: We conducted a single center retrospective study evaluating pts with CLL/SLL treated with zanubrutinib QD vs BID at Weill Cornell Medical Center (May 1, 2020 - Feb 1, 2025). Included CLL/SLL pts were treated with frontline zanubrutinib and separated into 3 groups: 320mg QD (Group 1), 160mg BID (Group 2) and dose switch (Group 3). Pearson’s Chi-squared test and Fisher’s exact test were used to compare baseline characteristics. Progression-free survival (PFS) and overall survival (OS) were evaluated with Kaplan-Meier (KM) method and log-rank test was used to compare KM curves; however, few events limited statistical power and prevented formal survival comparison and are presented as descriptive only. The median follow-up time was estimated by reverse KM method. Results: We identified 23 pts initiated on QD dosing, 43 pts initiated on BID dosing, and 33 pts who switched groups. Thirty pts switched from BID to QD and 3 pts from QD to BID. Median follow up time was 28.4 months. Median overall age was 71 with 60% male. There were no differences in age, sex, immunoglobulin heavy chain gene (IGHV) mutational status or incidence of complex karyotype, del11q, del13q, del17p, trisomy 12 and TP53 mutations. There was 1 death (Group 2) due to a second cancer. OS KM curves visually appeared similar (p=0.62). One pt in Group 2 and 2 pts in Group 3 progressed on zanubrutinib. PFS KM curves were visually similar (p=0.88). Twenty-two (22.2%) pts discontinued therapy due to intolerance. In Group 1, one pt (4.3%) discontinued for hypertension (HTN). In Group 2, 17/43 (39.5%) pts discontinued for rash (29.4%), infection (17.6%), bruising/bleeding (17.6%), HTN (11.7%), atrial fibrillation (11.7%) and diagnosis of second cancer (11.7%). In Group 3, 4/33 (12.1%) pts stopped for rash (50%) and HTN (50%). Zanubrutinib cessation was lower in QD vs BID (p < 0.002). Conclusions: We retrospectively compared QD vs BID dosing of zanubrutinib to evaluate impact on outcomes. While lack of progression and death limited our ability to make definitive statements on PFS or OS, we observed overlap of KM curves with 2 years of follow-up. We observed a lower treatment discontinuation rate with QD dosing. Our results suggest QD dosing in frontline CLL/SLL may improve tolerability while maintaining comparable efficacy. Further research is needed to confirm real-world non-inferiority of these safety and survival outcomes.