New data on bexobrutideg show that the treatment produced rapid and durable responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who had been heavily pretreated. The drug was well tolerated at several dose levels and treatment durations, and it was effective even in patients with mutations in the Bruton’s tyrosine kinase (BTK) gene and those with high-risk molecular features.
BTK inhibitors have been a major treatment advance in CLL, targeting the B-cell receptor (BCR) signaling pathway that is critical for the survival of malignant B cells. However, primary and acquired resistance to BTK inhibition can occur due to a variety of reasons, including gene mutations.
Bexobrutideg is a novel, highly selective, orally administered drug that degrades the BTK protein, a mechanism distinct from that of standard BTK inhibitors. The treatment is hypothesized to help overcome resistance to BTK inhibition.
The NX-5948-301 is a phase 1 first-in-human trial studying the medication in relapsed/refractory B-cell malignancies, including dose-escalation and dose-expansion cohorts of patients with CLL. The research team, led by Zulfa Omer of the University of Cincinnati in Ohio, presented early results from the dose-expansion cohort at the American Society of Hematology Annual Meeting and Exposition.
The cohort included patients who had received at least two prior therapies, had prior exposure to both a BTK inhibitor and a BCL-2 inhibitor, or were deemed ineligible to receive a BCL-2 inhibitor. The study team randomized participants to receive either 200 mg or 600 mg of bexobrutideg. Researchers assessed preliminary efficacy, safety, and tolerability, and they sought to establish a recommended dose.
As of the presentation, the study had enrolled 230 patients, including 97 with CLL. Of those, 42 were in the dose-expansion cohort. They had a median age of 68 years, had received a median of four prior lines of therapy, and had a variety of baseline mutations.
Median time to first response was 1.9 months, and responses deepened over time. At a median follow-up of 8.7 months, the overall response rate was 78.6%. One had a complete response, 60 had a partial response, and five had a partial response with lymphocytosis.
Patients tolerated the treatment well at all doses. The most common treatment-emergent adverse events were:
- Purpura/contusion: 38.1%; grade ≥3, 0%;
- Neutropenia: 29.9%; grade ≥3, 23.7%;
- Fatigue: 25.8%; grade ≥3, 1%;
- Diarrhea: 23.7%; grade ≥3, 2.1%;
- Headache: 23.7%; grade ≥3, 0%;
- Petechiae: 23.7%, grade ≥3, 0%; and
- Thrombocytopenia: 21.6%, grade ≥3, 3.1%.
No toxicities were dose-limiting, but five patients (5.2%) discontinued treatment due to an adverse event. No patients experienced systemic fungal infections, new-onset atrial fibrillation, or ventricular arrhythmia.
Reference Omer Z, Danilov A, Forconi F. 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 abs25-4184. Presented at: the 67th American Society of Hematology Annual Meeting and Exposition, Dec. 6-9, 2025, Orlando, FL.
