New phase 3 trial pits novel BTK degrader against pirtobrutinib in relapsed leukemia

A new global phase 3 trial is setting up a head-to-head matchup in one of hematology's toughest treatment landscapes. The DAYBreak CLL-306 trial (NCT07516093) will compare bexobrutideg — a highly selective small molecule BTK protein degrader — against pirtobrutinib in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have previously progressed on covalent BTK inhibitor (BTKi) therapy.

What makes bexobrutideg stand out? Unlike existing BTKi drugs, it degrades both wild-type and mutant forms of BTK, targeting both its kinase and scaffolding functions. Early phase 1 data showed it was well tolerated with rapid and durable responses, and the recommended phase 2 dose was set at 600 mg once daily.

Key Takeaways:

• ~620 adult patients will be randomized 1:1 to bexobrutideg (600 mg daily) or pirtobrutinib (200 mg daily) in continuous 28-day cycles
• Primary endpoint: progression-free survival assessed by an independent review committee
• Key secondary endpoints include health-related quality of life, safety, and pharmacokinetics
• Disease assessments will occur every 12 weeks until week 96, then every 24 weeks thereafter

Why it matters: BTKi resistance is a growing clinical challenge in CLL/SLL. By degrading the entire BTK protein — rather than just inhibiting its kinase activity — bexobrutideg could offer a meaningful new option for patients who have exhausted effective targeted therapies.