Paper Details

ABSTRACT

Background: Although Bruton’s tyrosine kinase (BTK) inhibition has been a successful treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the emergence of BTK inhibitor (BTKi) resistance mutations and kinase-independent signaling via the scaffolding function of BTK highlight a need for alternative treatments. Bexobrutideg (NX-5948) is a highly selective, orally administered small molecule degrader that causes the removal of wild-type and mutant forms of BTK through ubiquitination by the cereblon E3 ligase complex and subsequent proteasomal degradation. We report new and updated Phase 1a/b efficacy and safety data for patients with relapsed/refractory (R/R) CLL with no CNS involvement who were assigned to receive bexobrutideg 600 mg once daily, with a focus on patients with prior covalent BTKi (cBTKi) exposure.

Methods: NX-5948-301 (NCT05131022) is a first-in-human, Phase 1a/1b trial of the BTK degrader bexobrutideg in advanced B-cell malignancies including CLL, consisting of 3+3 dose-escalation (Phase 1a) followed by dose-expansion (Phase 1b) cohorts. We present safety data for patients with R/R CLL and efficacy data for patients with prior cBTKi exposure assigned to receive bexobrutideg 600 mg, the recommended Phase 2 dose (RP2D).

Results: As of April 1, 2026, 79 patients with R/R CLL without CNS involvement were treated with assigned bexobrutideg 600 mg (safety analysis set). The median age was 69 (range 41–83) years; 64.6% of patients were male; median prior lines of treatment 3.0 (range 1–15); 69 (87.3%) patients had prior BTKi exposure, including 66 (83.5%) with prior cBTKi exposure. With a median treatment duration of 8.0 (range 0.03–24.4) months, bexobrutideg 600 mg was well tolerated, consistent with previous reports. Reasons for discontinuation (n=24) were: radiographic progression (n=8); clinical progression (n=3); adverse event (n=7); death (n=1, not deemed treatment related); physician decision (n=3); and patient withdrawal of consent (n=2). Overall, treatment-emergent adverse events (TEAEs) were reported in 75 (94.9%) patients (75.9% treatment related). Grade ≥3 TEAEs were reported in 42 (53.2%) patients (26.6% treatment related). Serious TEAEs were reported in 24 (30.4%) patients (7.6% treatment related). The most frequent TEAEs were purpura/contusion (35.4%; no Grade ≥3), petechiae (31.6%; no Grade ≥3), neutropenia (29.1%; Grade ≥3 22.8%), and diarrhea (25.3%; no Grade ≥3). Three deaths were observed (pneumonia, acute respiratory distress syndrome, lymphoplasmacytic lymphoma), all classified as unrelated to bexobrutideg. The incidence of atrial fibrillation, Grade ≥3 fungal infections, and elevated amylase/lipase was low.

The efficacy dataset comprised patients with prior cBTKi exposure assigned to bexobrutideg 600 mg. Baseline demographics and clinical characteristics were similar to the safety analysis set and 43 patients remain on treatment. In the 61 response-evaluable patients with prior cBTKi exposure, median follow-up was 13.2 (range 2.6–24.4) months; the objective response rate (ORR) was 85.2% (2 CRs, 43 PRs and 7 PRs with lymphocytosis). The 18-month duration of response (DoR) event-free rate was 64.1% (95% CI 41.5–79.9%; median DoR not reached). The 18-month median progression-free survival (PFS) event-free rate was 52.9% (95% CI 33.3–69.1%; median PFS not reached). High ORRs were observed among BCL2 inhibitor (BCL2i)-naïve patients (n=31; ORR 83.9%, 95% CI 66.3–94.5%)?, double (cBTKi and BCL2i)-exposed (excluding triple-exposed) patients (n=21; ORR 95.2%, 95% CI 76.2–99.9%), and triple (cBTKi, non-covalent BTKi and BCL2i)-exposed patients (n=9; ORR 66.7%, 95% CI 29.9–92.5%). An update on the BTKi-naïve population and efficacy data in patients with high-risk molecular features will be presented.

Conclusions: The RP2D of bexobrutideg (600 mg) was well tolerated in R/R CLL. High ORRs were observed in patients with prior cBTKi exposure, including BCL2i-naïve, double-exposed, and triple-exposed patients. Ongoing evaluations include additional Phase 1 cohorts (BTKi-naïve, CNS involvement, and non-covalent BTKi-exposed) along with the pivotal Phase 2 DAYBreak CLL-201 and Phase 3 DAYBreak CLL-306 trials.