EHA 2026 | What are the most recent findings from the phase I NX-5948-301 trial evaluating bexobrutideg in CLL?

During the European Hematology Association (EHA) 2026 Congress, June 11–14, 2026, Stockholm, SE, the Lymphoma Hub was pleased to speak with Dr Talha Munir, Leeds Teaching Hospital, Leeds, UK. We asked, What are the most recent findings from the phase I NX-5948-301 trial evaluating bexobrutideg in chronic lymphocytic leukemia (CLL)? 

Key points¹ 

• Bexobrutideg is a Bruton’s tyrosine kinase (BTK) degrader that shows superior cell killing across common BTK mutations in CRISPR-engineered TMD8 cells compared with other BTK inhibitors (BTKis) and demonstrates selective degradation of BTK at clinically relevant exposures. 
• The ongoing phase Ia/b NX-5948-301 study (NCT05131022) is investigating bexobrutideg in relapsed/refractory (R/R) B-cell malignancies, including CLL and small lymphocytic lymphoma (SLL) (N = 142). 
• Phase Ia is a dose-escalation study that evaluated the safety and tolerability of bexobrutideg at doses 50–600 mg in R/R CLL/SLL. 
• In the phase Ib portion of the trial, patients with prior BTKi and B-cell lymphoma 2 inhibitor (BCL2i) exposure were randomized to receive 600 mg or 200 mg bexobrutideg.  
• In the phase Ib dose-expansion portion of the study, bexobrutideg is being evaluated in up to 17 expansion cohorts, including in patients treated at earlier lines of therapy, at the recommended phase II dose (600 mg). 
• Cohort 5 (C5) includes patients who have been exposed to BTKis but are BCL2i-naïve, and Cohort 15 (C15) includes patients who are BTKi-naïve or treatment-naïve. 
• At 22.4 months follow-up, in the phase Ia portion of the trial (n = 48), the objective response rate (ORR) was 83.0%, with a complete response in 4% of patients. The median progression-free survival (PFS) was 22.1 months. 
• In phase Ib, the ORRs in cohorts C5 and C15 were as follows: 
  • Cohort C5: At 5.2 months follow-up, the ORR was 92.9% (n = 19). 
  • Cohort C15: At 4.9 months follow-up, the ORR was 84.2% (n = 20). 
• Lymph node size decreases were observed regardless of prior treatments or mutational burden at baseline. 
• Overall (N = 142), treatment-emergent adverse events (TEAEs) of any grade occurred in 94.4% of patients; 77.5% were treatment-related. 
• Grade ≥3 TEAEs were reported in 51.4% of patients, with 24.6% being treatment-related, and Grade 5 TEAEs occurred in 3% of patients.  
• No dose-limiting toxicities were observed at any dose level. 
• The most common TEAE was purpura/contusion, followed by neutropenia, petechiae, and diarrhea. 
• These data support the further clinical development of bexobrutideg; the phase II DAYBreak-201 study (NCT07221500) is ongoing, with the phase III DAYBreak-306 study due to initiate in 2026.  

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