Bexobrutideg Shows High Response Rates and Manageable Safety in BTK Degrader Trial for Relapsed/Refractory CLL
Key Insights
Bexobrutideg (search), a BTK (search) degrader, demonstrated an 83% objective response rate in the phase Ia dose-escalation portion of the NX-5948-301 trial in heavily pretreated R/R CLL/SLL patients at 22.4 months follow-up.
In phase Ib expansion cohorts, ORRs reached 92.9% in BTKi-exposed/BCL2i-naïve patients and 84.2% in BTKi-naïve or treatment-naïve patients, with lymph node reductions observed regardless of prior treatment.
The most common treatment-emergent adverse event was purpura/contusion; no dose-limiting toxicities were observed at any dose level, and grade ≥3 treatment-related TEAEs occurred in 24.6% of patients.
Bexobrutideg (search) (NX-5948), an investigational Bruton's tyrosine kinase (BTK (search)) degrader, has demonstrated compelling clinical activity and a manageable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia (search) and small lymphocytic lymphoma (search) (R/R CLL/SLL), according to updated findings from the phase I NX-5948-301 trial presented at the European Hematology Association (EHA) 2026 Congress in Stockholm, Sweden.
The data, discussed by Dr. Talha Munir of Leeds Teaching Hospital, UK, highlight the potential of bexobrutideg (search) as a novel therapeutic approach that leverages targeted protein degradation rather than enzymatic inhibition to address BTK (search)-driven malignancies, including in patients with common BTK resistance mutations.
Mechanism of Action and Preclinical Rationale
Bexobrutideg (search) functions as a BTK (search) degrader, a mechanism distinct from conventional BTK inhibitors (BTKis). Preclinical data show that bexobrutideg achieves superior cell killing across common BTK mutations in CRISPR-engineered TMD8 cells compared with other BTKis, and demonstrates selective degradation of BTK at clinically relevant exposures. This degradation-based approach may offer advantages in overcoming resistance mutations that emerge during treatment with covalent and non-covalent BTK inhibitors.
Phase Ia Dose-Escalation Results
The ongoing phase Ia/b NX-5948-301 study (NCT05131022) is evaluating bexobrutideg (search) in patients with R/R B-cell malignancies, including CLL and SLL, with a total enrollment of 142 patients. The phase Ia portion employed a dose-escalation design assessing safety and tolerability of bexobrutideg at doses ranging from 50 mg to 600 mg in patients with R/R CLL/SLL.
At a median follow-up of 22.4 months in the phase Ia cohort (n = 48), the objective response rate (ORR) reached 83.0%, with complete responses observed in 4% of patients. The median progression-free survival (PFS) was 22.1 months, underscoring durable disease control in a heavily pretreated population.
Phase Ib Dose-Expansion Cohorts
The phase Ib portion randomized patients with prior exposure to both BTKis and BCL2 inhibitors (BCL2i) to receive either 600 mg or 200 mg of bexobrutideg (search). Additionally, the dose-expansion phase includes up to 17 cohorts evaluating bexobrutideg at the recommended phase II dose of 600 mg across earlier lines of therapy.
Key efficacy findings from two notable expansion cohorts include:
- Cohort 5 (C5) — patients with prior BTKi exposure but BCL2i-naïve: At 5.2 months follow-up, the ORR was 92.9% (n = 19).
- Cohort 15 (C15) — patients who are BTKi-naïve or treatment-naïve: At 4.9 months follow-up, the ORR was 84.2% (n = 20).
Notably, decreases in lymph node size were observed regardless of prior treatments or baseline mutational burden, suggesting broad activity across clinically relevant subgroups.
Safety Profile
Across the overall study population (N = 142), treatment-emergent adverse events (TEAEs) of any grade occurred in 94.4% of patients, with 77.5% deemed treatment-related. Grade ≥3 TEAEs were reported in 51.4% of patients, of which 24.6% were treatment-related. Grade 5 TEAEs occurred in 3% of patients.
Importantly, no dose-limiting toxicities were observed at any dose level tested. The most common TEAE was purpura/contusion, followed by neutropenia, petechiae, and diarrhea.
Future Development
These data support the continued clinical advancement of bexobrutideg (search). The phase II DAYBreak-201 study (NCT07221500) is currently ongoing, and the phase III DAYBreak-306 trial is expected to initiate in 2026, marking a significant step toward potential registration of this first-in-class oral CELMoD agent in CLL.