Pb1926: efficacy and safety of once daily (qd) vs twice daily (bid) zanubrutinib for patients with various b-cell malignancies: a comparative summary of clinical data and exposure-response analyses

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: Zanubrutinib (320 mg QD or 160 mg BID) is a next-generation irreversible Bruton tyrosine kinase (BTK) inhibitor approved in various countries for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). While both QD and BID doses were studied in select phase 1 and 2 zanubrutinib trials, only the BID dose has been used in pivotal clinical studies to date. Thus, a summary of clinical data and analyses between the 2 schedules across various B-cell malignancies is of interest. Aims: We aimed to conduct a comparative summary of safety and efficacy data between the QD and BID regimens in patients with various B-cell malignancies. In addition, exposure-response (E-R) analyses for safety and efficacy endpoints were conducted to bridge the QD and BID regimen. Methods: Patients from 5 studies were included in the analysis (monotherapy: BGB-3111-AU-003, BGB-3111-215, BGB-3111-216, BGB-3111-1002; combination with obinutuzumab: BGB-3111-GA-101). The following safety and efficacy endpoints were analyzed: adverse events of special interest (AESI), disease response (overall response rate [ORR], complete response [CR] rate or complete metabolic response, and rate of very good partial response [VGPR] or better for WM). The incidence and severity of AESI were prespecified based on the known toxicity for the BTK inhibitor class, including infections, bleeding, hypertension, atrial fibrillation/flutter, and peripheral blood cytopenias. For the E-R analyses, a population pharmacokinetic (PK) model predicted individual area under the curve (AUC), peak concentration (Cmax), and minimum observed concentration (Cmin) values, which were merged with corresponding safety or efficacy data. Then, exposure-efficacy and safety relationships were assessed (eg, probability of response plots and logistic regression model) in patients with MCL, WM, MZL, CLL/SLL and follicular lymphoma (FL) from the 5 zanubrutinib studies described. Results: A total of 216 patients with various B-cell malignancies receiving zanubrutinib 320 mg QD were identified across 5 studies. There are no marked differences in objective responses observed using QD or BID doses in patients across various indications; while there was a numerical difference, the confidence intervals were overlapping (a subset of efficacy evaluable population, with N≥5 in each indication is summarized [Table]). Similar to the previous report (Ou et al. Leuk Lymphoma 2021), comparable safety profiles were observed with both dosing schedules. In 278 patients receiving zanubrutinib BID vs 95 receiving zanubrutinib QD from the BGB-3111-AU-003 study, respectively, rates of ≥1 AE leading to treatment discontinuation (11.2% vs 8.4), grade ≥3 hemorrhage (4.0% vs 3.2%), grade ≥3 hypertension (4.0% vs 2.1%), and grade ≥3 atrial fibrillation/flutter (1.4% vs 1.1%) were comparable. There were no evident E-R relationships between PK exposure (AUC, Cmax, or Cmin) and efficacy endpoints or the probability of having an AESI across indications. Overall, the E-R analysis showed that ORR and adverse event rate was not impacted by Cmax or Cmin differences between the QD and BID regimens that have the same total daily dose and AUC. Summary/Conclusion: Both 320 mg QD and 160 mg BID are safe and effective regimens with high rates of objective response in patients with various B-cell malignancies. Comparison of the ORR between QD and BID dosing did not indicate advantage of either regimen.Keywords: Non-Hodgkin’s lymphoma, Tyrosine kinase inhibitor, Pharmacokinetic