Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in Relapsed/Refractory chronic lymphocytic leukemia (CLL): New and updated findings from an ongoing Phase 1a/b trial

Abstract

Abstract Introduction: Although BTK inhibition has proven to be a successful treatment modality in CLL, the emergence of BTK inhibitor (BTKi) resistance mutations and identification of kinase-independent signaling via the scaffolding function of BTK underscore the need for alternative approaches to target the totality of BTK protein functions. Bexobrutideg is a novel, highly selective, orally administered small molecule degrader that induces 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 findings from patients (pts) with relapsed/refractory CLL in a Phase 1 (Ph1) trial of bexobrutideg, including longer-term follow-up from the Ph1a cohort combined with first disclosure from the randomized Ph1b cohort. Methods: NX-5948-301 is a Ph1, first-in-human trial of bexobrutideg in relapsed/refractory B-cell malignancies, including CLL, consisting of 3+3 dose-escalation (Ph1a) followed by dose-expansion (Ph1b) cohorts. In Ph1b Cohort 1, pts were randomized between the 200 mg and 600 mg dose levels. Key eligibility criteria include ≥2 prior therapy lines (Ph1a) or prior exposure to both a BTKi and BCL2i (or deemed ineligible for BCL2i) (Ph1b). Primary objectives are evaluation of safety/tolerability and identification of a recommended Ph2 dose. Key secondary objectives include characterization of the PK/PD profile and assessment of preliminary efficacy. Results: As of 27 May 2025, 230 pts have been enrolled across all indications, including 97 pts with CLL/SLL enrolled in the Ph1a and Ph1b cohorts. Pts were enrolled at 6 daily oral dose levels: 50 mg (n=3), 100 mg (n=5), 200 mg (n=33), 300 mg (n=8), 450 mg (n=7), 600 mg (n=41), including 42 pts in the Ph1b cohort randomized into 200 mg and 600 mg. Median age was 68 (range 35–88) years; pts had received a median of 4 (range 1–12) prior lines of therapy, including: covalent BTKi (cBTKi, 97.9%), non-covalent BTKi (ncBTKi, 32.0%), BCL2i (74.2%), BTKi+BCL2i (73.2%), chemo/chemoimmunotherapy (77.3%), PI3Ki (24.7%), and CAR-T (6.2%). In 85 pts with genetic testing available, baseline mutations included BTK (42.4%), PLCG2 (10.6%), and TP53 (42.4%). BTK mutations with VAF >5% spanned C481S (n=19), C481R (n=3), T474 (n=12), L528 (n=8), and V416 (n=1). Bexobrutideg was well tolerated across all doses in pts from the Ph1a/b CLL cohorts, consistent with previous reports. Median follow-up was 8.7 (0.3–28.6) months (mo). The most common treatment-emergent adverse events (TEAEs) were: purpura/contusion (38.1%; Grade (Gr) ≥3, 0%); neutropenia (29.9%; Gr ≥3, 23.7%); fatigue (25.8%; Gr ≥3, 1.0%); diarrhea (23.7%; Gr ≥3, 2.1%), headache (23.7%; Gr ≥3, 0%); petechiae (23.7%, Gr ≥3, 0%), and thrombocytopenia (21.6%, Gr ≥3, 3.1%). There were no dose-limiting toxicities, and 5 pts (5.2%) discontinued treatment due to a TEAE (Gr 2 pre-syncope, Gr 2 dysphagia, Gr 2 hot flush, Gr 3 pneumonia and sepsis and Gr 4 neutrophil count decreased, Gr 5 pneumonia on cycle 1, deemed not related to treatment). No systemic fungal infections or new onset atrial fibrillation or ventricular arrhythmias were observed. In the 84 response-evaluable Ph1a/b pts with CLL/SLL the ORR was 78.6% (1 CR, 60 PR and 5 PR-L). Median time to first response was 1.9 (range 1.6–11.1) mo; median duration of response was not reached (95% CI 12.2 mo–not reached). Responses deepened over time, with 15 pts converting from SD to PR and 1 pt from PR to CR. Twenty pts reached >12 mo on study (19/20 still on treatment, 1 bridged to allo transplant), and 6 pts >18 mo (all still on treatment); 69/97 pts remained on study including 4/5 pts with CNS involvement. Results from next-generation sequencing for BTK mutations including kinase dead mutations (L528W, V416L and A428D) and kinase proficient T474 will be presented as well as efficacy in clinically meaningful subgroups. Conclusions:In the largest Ph1a/b cohort of pts with relapsed/refractory CLL treated with bexobrutideg reported to date, bexobrutideg was well tolerated across dose levels and treatment durations. Bexobrutideg showed rapid and durable responses in a heavily pre-treated population of pts with CLL, including those with baseline BTK mutations and high-risk molecular features. Additional follow-up and preliminary results from the 200 mg vs 600 mg randomized dose-expansion cohorts will be presented.