Phase 2 zanubrutinib (BTK inhibitor) + sonrotoclax (BCL-2 inhibitor) in relapsed CLL/SLL

City of Hope Medical Center is running ZeuS-2, a Phase 2, fixed-duration, all-oral combination study evaluating zanubrutinib (a covalent Bruton tyrosine kinase inhibitor that blocks B-cell receptor signaling) with sonrotoclax/BGB-11417 (a BH3-mimetic BCL-2 inhibitor program often described publicly as BCL-2–targeting) in CLL/SLL at first relapse after prior fixed-duration “novel therapy.” Patients start with zanubrutinib alone for cycles 1–4, then add sonrotoclax from cycle 5 onward, continuing in 28-day cycles for up to 24 total cycles, with serial imaging and marrow/blood sampling for response and MRD-type translational readouts. The scientific/commercial angle is whether a second fixed-duration, chemo-free, time-limited doublet can recapture deep remissions after patients relapse following first-line fixed-duration targeted regimens—an increasingly common real-world sequence. Today’s care for relapsed CLL/SLL after prior time-limited targeted therapy is typically continuous BTK inhibition (e.g., zanubrutinib class) or a venetoclax-based approach (BCL-2 inhibition) chosen by prior exposure, resistance, and tolerability; this trial tests a next-generation BTK + BCL-2 backbone in that specific post–fixed-duration setting.