Bexobrutideg Shows Rapid, Durable Responses in Relapsed/Refractory CLL in Updated Phase 1a Trial Data
Key Highlights
• Bexobrutideg was well tolerated across all dose levels with no dose-limiting toxicities.
• The overall response rate reached 80.9% among response-evaluable patients, with a rapid onset of response.
• Responses were durable and observed irrespective of mutation status or prior therapy exposure.
• Safety signals included mainly low-grade purpura, diarrhea, fatigue, and rash.
Investigators of a global Phase 1a study presented at the Lymphoma, Leukemia, and Myeloma Congress 2025 in New York City, New York, reported updated safety and efficacy findings for bexobrutideg (NX-5948), a first-in-class, orally administered Bruton's Tyrosine Kinase (BTK) degrader designed to eliminate both wild-type and mutant BTK through cereblon-mediated ubiquitination and proteasomal degradation. Given accumulating resistance to covalent and noncovalent BTK inhibitors in relapsed/refractory chronic lymphocytic leukemia (CLL), the investigators aimed to assess whether targeted BTK degradation could overcome kinase-independent resistance mechanisms.
NX-5948-301 is a Phase 1, first-in-human, multicenter trial enrolling patients with relapsed/refractory B-cell malignancies, including CLL and non-Hodgkin lymphoma. Phase 1a followed a parallel 3+3 dose-escalation design across 6 daily oral dose levels (50–600 mg). Eligible patients had received 2 or more prior lines of therapy and had an Eastern Cooperative Oncology Group performance status of 0-1. Primary objectives included safety and the determination of the recommended Phase 2 dose; secondary objectives included pharmacokinetics, pharmacodynamics, and preliminary efficacy based on iwCLL criteria.
Study Findings
As of the March 12, 2025, data cutoff, the Phase 1a CLL cohort (n = 48) was fully enrolled. Patients were heavily pretreated, with a median of 4 prior therapy lines. Most had previous exposure to covalent BTKi (97.9%) and BCL2 inhibitors (83.3%), and nearly half had TP53 mutations (44.7%). Additional mutations included BTK (38.3%), PLCG2 (14.9%), and BCL2 (12.8%).
Bexobrutideg demonstrated a favorable safety profile with no dose-limiting toxicities and only one discontinuation due to a treatment-emergent adverse event. Common adverse events included purpura/contusion (45.8%), diarrhea (31.3%), fatigue (31.3%), neutropenia (29.2%), rash (27.1%), petechiae (25.0%), and headache (25.0%). Grade ≥ 3 events were infrequent, and no occurrences of systemic fungal infection or new-onset atrial fibrillation were reported. One Grade 5 pulmonary embolism, deemed unrelated to treatment, occurred in a patient with atrial fibrillation.
Among 47 response-evaluable patients, the overall response rate was 80.9% (1 complete response; 37 partial responses). The responses emerged rapidly, with a median time to first response of 1.9 months. The median duration of response has not yet been reached. A total od 18 patients remained on the study for more than 12 months and 5 for more than 18 months. Responses were durable across mutation subsets and prior treatment exposures, including patients with high-risk features and central nervous system involvement.
Clinical Implications
According to the investigators, these results suggest that bexobrutideg may address resistance pathways unrelated to BTK kinase activity and provide a well-tolerated therapeutic option for patients with relapsed/refractory CLL, including those with extensive prior therapy or high-risk molecular characteristics.
Expert Commentary
“Bexobrutideg was well tolerated in patients with R/R CLL, including those with longer duration of treatment and higher doses,” the investigators concluded. ‘Bexobrutideg showed rapid and durable responses independent of prior treatment or high-risk features.”
Reference
Danilov A, Omer Z, Forconi F, et al. Bexobrutideg (NX-5948), a novel BTK degrader, demonstrates rapid and durable clinical responses in relapsed/refractory CLL: updated findings from ongoing Phase 1a study. Presented at: Lymphoma, Leukemia, and Myeloma Congress 2025; October 14–17, 2025; New York, NY. Accessed December 10, 2025. https://www.hmpgloballearningnetwork.com/node/347786.