C040 | Bexobrutideg (nx-5948), a Novel Bruton’s Tyrosine Kinase Degrader, Demonstrates Rapid and Durable Clinical Responses in Relapsed/refractory Chronic Lymphocytic Leukemia Updated Findings From an Ongoing Phase 1a Study
Year: 2025
Type: article
Abstract: Bexobrutideg is a novel, 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 updated Phase 1a findings of bexobrutideg in patients with R/R CLL. NX-5948-301 is a Phase 1, first-in-human trial in R/R B-cell malignancies with parallel 3+3 dose-escalation (1a) and dose-expansion (1b) cohorts. Key eligibility criteria: ≥2 prior lines of therapy (LoT) and ECOG PS 0–1. Primary objectives: safety/tolerability and identification of a recommended Phase 2 dose. Key secondary objectives: PK/PD and preliminary efficacy. As of 2 January 2025, the fully enrolled Phase 1a cohort included 48 patients with CLL/SLL treated at 6 dose levels p.o. daily: 50 mg (n=3), 100 mg (n=5), 200 mg (n=9), 300 mg (n=8), 450 mg (n=7), 600 mg (n=16). Median age 68.5 (range 35–88) years; 66.7% male; median 4 (range 2–12) prior LoT, including: cBTKi (97.9%), ncBTKi (27.1%), BCL2i (83.3%), BTKi+BCL2i (81.3%), chemo/chemoimmunotherapy (72.9%), PI3Ki (29.2%), and CAR-T (6.3%). In 47 patients with genetic testing data, mutations were: TP53 (44.7%), BTK (38.3%), PLCG2 (14.9%), and BCL2 (12.8%). Bexobrutideg was well tolerated across all doses. The median duration of treatment was 7.0 (0.2–23.8) months. There were no DLTs; 1 patient discontinued due to a TEAE. The most common TEAEs were: purpura/contusion (41.7%, no Gr≥3); fatigue (31.3%, no Gr≥3); neutropenia (29.2%, 22.9% Gr≥3); rash (29.2%, 2.1% Gr≥3, 2.1% SAE), diarrhea (29.2%; 4.2% Gr≥3), and petechiae (25.0%, no Gr≥3). One Grade 5 event occurred that was considered unrelated to bexobrutideg. No systemic fungal infections or new onset atrial fibrillation were observed. In 47 response-evaluable patients, the ORR was 80.9% (all PR). Median time to first response was 1.9 (range 1.6–11.1) months. Median duration of response has not been reached. Thirteen patients have reached >12 months on study, and 5 patients >18 months. Durable responses were seen regardless of prior treatments, mutations in TP53, PLCG2, BCL2 and BTK (including kinase active and kinase dead), or CNS involvement. Bexobrutideg was well tolerated in patients, including those with longer duration of treatment and higher doses. Rapid and durable responses were observed independent of prior treatment or high-risk features. Phase 1b dose expansion (200 and 600 mg cohorts) is underway with plans to initiate pivotal trials in 2025.
Authors: P. Zinzani, Z. Omer, A. Danilov, F. Forconi, N. Shah, G. Collins, S. Ma, J. Robertson, A. Alencar, D. Brander, J. Byrd, D. El-Sharkawi, J. Smith, A. Winter, M. Kwiatek, J. Cohen, P. Islam, S. Injac, T. Munir
Institutions: University of Bologna, University of Cincinnati, City Of Hope National Medical Center, University Hospital Southampton NHS Foundation Trust, Medical College of Wisconsin, University of Oxford, Northwestern University, The Christie Hospital, Cancer Research UK Manchester Centre, Sylvester Comprehensive Cancer Center, Duke University, Duke Cancer Institute, Royal Marsden NHS Foundation Trust, Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Hospital, Cleveland Clinic, Emory University, Winship Cancer Institute, Memorial Sloan Kettering Cancer Center, Nurix (United States), St. James's Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7093123148
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