Updated efficacy and safety data from an ongoing phase 1a/b trial of the Bruton's tyrosine kinase (BTK) degrader bexobrutideg (NX-5948) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) across lines of therapy
Materials and Methods/Case Presentation/Objective: NX-5948-301 (NCT05131022) is a Ph1, first-in-human trial of bexobrutideg in advanced B-cell malignancies. In CLL/SLL, bexobrutideg is being evaluated in R/R patients from the Ph1a dose-escalation part and then in Ph1b dose-expansion cohorts that include heavily pre-treated, earlier-line and treatment-naïve patients. Safety is presented for all patients with CLL/SLL. Efficacy is presented for all Ph1a dose-escalation patients and for selected Ph1b dose-expansion cohorts treated at the recommended Ph2 dose (RP2D) of 600 mg: Cohort 1 (C1; primarily BTKi and BCL2i exposed), C5 (BTKi-exposed and BCL2i-naïve), and C15 (BTKi-naïve, including treatment-naïve patients).
Results/Description/Main Outcome Measure(s):
As of 1 Jan 2026, 142 CLL/SLL patients have been enrolled (48 to Ph1a; 42 to Ph1b C1; 19 to Ph1b C5; and 20 to Ph1b C15 with 10 treatment-naive). Ph1a and Ph1b C1 had a median 4 and 5 prior LoT respectively, while Ph1b C5 and Ph1b C15 had a median 2 and 1 prior LoT, respectively.
Bexobrutideg continues to be well tolerated in patients treated across all doses (n=142), including in 86 patients treated at 600 mg. The safety profile was maintained over the duration of treatment and across different prior LoT with most adverse events (AEs) being grade 1/2. The most common treatment-emergent AEs included purpura/contusion, neutropenia, and petechiae.
A high objective response rate (ORR) was observed across all cohorts irrespective of prior therapies: Ph1a 83.0% (22.4 months follow-up); Ph1b C1 (BTKi/BCL2i exposed) 83.3% at 600 mg (13.1 months follow-up); Ph1b C5 (BTKi-exposed/BCL2i naïve) 86.7% (5.3 months follow-up); Ph1b C15 (BTKi-naïve including treatment naïve) 84.2% (4.9 months follow-up). The high ORRs in Ph1b C5 and Ph1b C15 are notable, given the short duration of treatment and follow-up. Lymph node size decreases were observed regardless of prior treatments or mutational burden at baseline. Median progression-free survival (mPFS) was 22.1 months in Ph1a (mPFS follow-up 19.8 months).
Conclusion(s).: In this Ph1a/b trial, bexobrutideg demonstrated a favorable safety profile in patients with CLL/SLL with longer follow-up across doses and prior treatments. Durable responses were maintained in the Ph1a dose-escalation cohort, which has the longest follow-up to date. High response rates were observed across populations with different prior therapies, including in patients previously treated with BTKi and in BTKi-naïve patients, supporting further clinical development. Bexobrutideg is being evaluated in the Ph2 DAYBreak-201 study (NCT07221500) and a Ph3 DAYBreak-306 study investigating bexobrutideg vs pirtobrutinib is planned.
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