Phase 3 DAYBreak CLL-306 compares bexobrutideg BTK degradation with pirtobrutinib after covalent BTK inhibition

Nurix Therapeutics’ randomized, open-label, multicenter DAYBreak CLL-306 study compares bexobrutideg (NX-5948), a small-molecule Bruton tyrosine kinase protein degrader, with pirtobrutinib, Eli Lilly’s noncovalent BTK inhibitor, in relapsed or refractory CLL/SLL after covalent BTK-inhibitor therapy. The study excludes previous treatment with a BTK degrader or noncovalent BTK inhibitor, preserving a direct comparison of these approaches in the intended post-covalent-BTKi population.

Bexobrutideg is designed to remove BTK protein rather than merely inhibit its kinase activity, potentially addressing resistance that limits inhibitor binding. The Phase 3 comparison tests whether that mechanism translates into better clinical outcomes against an established oral option; mechanistic differences alone cannot establish superiority. Treatment after covalent BTKi failure also depends on prior venetoclax exposure, molecular features, fitness, and access to cellular therapies. This study provides a clinically relevant head-to-head test rather than a comparison against an outdated chemoimmunotherapy control.