Combination Treatment with Sonrotoclax (BGB-11417), a Second-Generation BCL2 Inhibitor, and Zanubrutinib, a Bruton Tyrosine Kinase (BTK) Inhibitor, Is Well Tolerated and Achieves Deep Responses in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (TN-CLL/SLL): Data from an Ongoing Phase 1/2 Study

Background: The combination of BCL2 and BTK inhibitors has shown synergistic activity. The combination of venetoclax, a BCL2 inhibitor, and ibrutinib, a BTK inhibitor, is an effective treatment for CLL/SLL. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. Zanubrutinib, a next-generation BTK inhibitor, has shown improved PFS with fewer cardiac adverse events (AEs) vs ibrutinib in a randomized study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). BGB-11417-101 (NCT04277637) is an ongoing, first-in-human, phase 1/1b dose-escalation/expansion study of patients with various B-cell malignancies. In a preliminary report, sonrotoclax, alone or in combination with zanubrutinib, was well tolerated at all doses tested up to 640 mg. This abstract describes the safety and efficacy data from patients with treatment-naïve (TN) CLL/SLL who received the combination of sonrotoclax and zanubrutinib. Methods:Patients received zanubrutinib (320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax using a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg QD (doubling weekly [W] or 30% increase every day 5 d/week [D]) to mitigate risk of tumor lysis syndrome (TLS). Patients were treated until progression, unacceptable toxicity, or could elect to stop. TLS was assessed per Howard (2011) criteria; mitigation included mandatory oral hydration and antihyperuricemics. Primary endpoint was safety (reported per CTCAEs v5.0); a secondary endpoint was ORR (per iwCLL 2008 criteria) and minimal residual disease assessed in blood by ERIC flow every 24 weeks (uMRD4;