Bexobrutideg Produces High Response Rates Across Treatment Lines in CLL/SLL

The BTK degrader bexobrutideg (NX-5948) produced responses across lines of therapy, including in the treatment-naive setting, in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to updated findings from the phase 1a/b NX-5948-301 trial (NCT05131022) presented at the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting.

Findings from the phase 1a, dose-escalation portion of the study showed that patients with relapsed/refractory CLL/SLL (n = 47) achieved an overall response rate (ORR) of 83.0% (95% CI, 69.2%-92.4%), including a complete response (CR) rate of 4.3%. At a median follow-up of 22.4 months (range, 16.9-35.7), a median progression-free survival was 22.1 months (95% CI, 14.0-not reached).

In the phase 1b portion, the selective BTK degrader generated an ORR of 92.9% (95% CI, 66.1%-99.8%) in cohort 5, which included patients with BTK inhibitor–treated, BCL2 inhibitor–naive disease (n = 14) and an ORR of 84.2% (95% CI, 60.4%-96.6%) in cohort 15, which featured patients with BTK inhibitor–naive disease, including those who were treatment naïve; all responses in both of these cohorts were partial. Notably, follow-up for these patients was limited, at 5.2 months (range, 1.9-7.7) for cohort 5 and 4.9 months (range, 2.9-5.8) for cohort 15. Responses were observed across difficult-to-treat subgroups, and the agent was generally well tolerated across the evaluated doses.

“Based on the totality and consistency of safety and efficacy findings, bexobrutideg is being evaluated in the ongoing pivotal phase 2 DAYBreak CLL-201 [NCT07221500] and planned phase 3 DAYBreak CLL-306 [NCT07516093] trials,” lead study author Zulfa Omer, MD, an assistant professor of clinical medicine at the University of Cincinnati College of Medicine in Ohio, and colleagues wrote in a poster presentation of the data.

What is the mechanism of action of bexobrutideg?

The current and most accepted care for patients with CLL focuses on utilizing BTK and BCL2 inhibitors; however, BTK resistance mutations stemming from treatment with covalent and noncovalent inhibitors are found in more than half of patients who progress on these therapies, and a growing number of patients are refractory to both BTK and BCL2 inhibitors.

The BTK degrader bexobrutideg is designed to yield specific degradation of both wild-type and mutated forms of BTK, and ubiquitination via the cereblon E3 ligase complex and subsequent proteasomal degradation are intended to overcome BTK resistance mutations stemming from prior treatment.

Who was eligible for the phase 1a and 1b portions of the NX-5948-301 trial?

To be eligible for enrollment in the phase 1a portion, patients needed to have relapsed/refactory CLL/SLL. In the phase 1b dose-expansion portion, cohort 5 enrolled patients who had received at least 1 prior line of therapy containing a BTK inhibitor and were BCL2 inhibitor naive. Cohort 15 enrolled BTK inhibitor–naive patients, including those who were treatment naive.

Across the study, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, measurable disease according to applicable disease-specific criteria, and adequate organ and bone marrow function.²

In phase 1a, bexobrutideg was evaluated at once-daily doses ranging from 50 mg to 600 mg.¹ Phase 1b also included a randomized cohort, where patients with relapsed/refractory CLL/SLL who received prior treatment a BTK inhibitor and BCL2 inhibitor were randomly assigned to receive bexobrutideg at 600 mg per day or 200 mg per day. All patients in cohort 5 and cohort 15 received the BTK degrader at 600 mg per day.

In the phase 1a dose-escalation portion of NX-5948-301, the primary end points were safety and tolerability and the identification of a recommended phase 2 dose. Secondary end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. according to International Workshop on CLL criteria. In the phase 1b dose-expansion portion, the primary end points were antitumor activity and safety/tolerability. Secondary end points included further characterization of the agent’s pharmacokinetic and pharmacodynamic profiles along with antitumor activity.

What are the patient characteristics in this trial?

At baseline, the median ages were 68.5 years (range, 35-88) for phase 1a (n = 48), 71.0 years (range, 48.0-79.0) for cohort 5 in phase 1b (n = 19), and 69.5 years (range, 41.0-87.0), for cohort 15 in phase 1b (n = 20). Men comprised 66.7%, 84.2%, and 50.0% of the respective cohorts, and 87.5%, 94.7%, and 95.0% of patients were White, respectively. ECOG performance statuses of 0 and 1 were reported at respective rates of 39.6% and 60.4% of patients in phase 1a, 63.2% and 36.8% of those in cohort 5, and 25.0% and 75.0% of those in cohort 15. Central nervous system involvement was present in 10.4% of patients in phase 1a and no patients in the phase 1b cohorts.

Patients in phase 1a received a median of 4.0 prior lines of therapy (range, 2-12). In this cohort, 97.9% had received a prior BTK inhibitor, including covalent and noncovalent BTK inhibitors in 97.9% and 27.1% of patients, respectively, and 83.3% had received a BCL2 inhibitor. Additionally, 81.3% had received both a BTK inhibitor and BCL2 inhibitor, 22.9% had received covalent and noncovalent BTK inhibitors and a BCL2 inhibitor, and 72.9% had received chemotherapy or chemoimmunotherapy.

In cohort 5, all patients received a prior covalent BTK inhibitor, 5.3% received a noncovalent BTK inhibitor, and 47.4% had received chemotherapy or chemoimmunotherapy. In cohort 15, no patients had received a BTK inhibitor, 10.0% had received a BCL2 inhibitor, and 40.0% had received chemotherapy or chemoimmunotherapy.

Among patients with evaluable mutation data, BTK, TP53, PLCG2, and BCL2 alterations were detected in 38.3%, 44.7%, 14.9%, and 12.8% of patients in phase 1a (n = 47), respectively; these respective rates were 52.6%, 47.4%, 15.8%, and 5.3% in cohort 5 (n = 19), and 0%, 15.0%, 0%, and 0% in cohort 15 (n = 20). Unmutated IGHV was identified in 85.3% of evaluable patients in phase 1a and 93.3% of 15 evaluable patients in cohort 5; neither of the 2 evaluable patients in cohort 15 had unmutated IGHV.

What is the safety profile of bexobrutideg?

In the safety population, which included patients with CLL/SLL treated across all evaluated doses (n = 142), 94.4% experienced at least 1 treatment-emergent adverse effect (TEAE), and 77.5% experienced a treatment-related TEAE. Grade 3 or higher TEAEs occurred in 51.4% of patients, and they were considered treatment related in 24.6%. Serious AEs were reported in 23.2% of patients, including treatment-related serious AEs in 6.3%. Grade 5 AEs occurred in 2.1% of patients, although none were treatment related.

Among the patients treated with the recommended phase 2 dose of 600 mg (n = 86), any-grade and treatment-related TEAEs occurred in 91.9% and 75.6% of patients, respectively. Grade 3 or higher TEAEs were reported in 45.3% of patients and were treatment related in 25.6%. Serious AEs occurred in 18.6% of patients and were treatment related in 5.8%. Among the patients treated at doses ranging from 50 mg to 450 mg (n = 56), these respective rates were 98.2%, 80.4%, 60.7%, 23.2%, 30.4%, and 7.1%. Grade 5 AEs were reported in 1.2% of patients treated at 600 mg and 3.6% of patients treated at lower doses. The median treatment exposure was 7.3 months (range, 0.03-35.8) overall, 5.1 months (range, 0.03-21.5) in the 600-mg group, and 12.5 months (range, 0.2-35.7) in the lower-dose group.

TEAEs led to treatment discontinuation in 5.6% of patients overall, including 5.8% of those who received 600 mg and 5.4% of those treated at lower doses. Treatment-related TEAEs led to discontinuation in 4.2%, 3.5%, and 5.4% of patients, respectively. The most frequently reported TEAEs included purpura or contusion, neutropenia, and petechiae. No dose-limiting toxicities were observed.

References

1. Omer Z, Munir T, Grosicki S, et al. Updated efficacy and safety data from an ongoing phase 1a/b trial of the Bruton’s tyrosine kinase (BTK) degrader bexobrutideg (NX-5948) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) across lines of therapy. Poster presented at: 2026 Society of Hematologic Oncology; September 9-12, 2026; Houston, TX. Abstract CLL-427.
2. A study of NX-5948 in adults with relapsed/​refractory B-cell malignancies. ClinicalTrials.gov. Updated July 2, 2026. Accessed September 14, 2026. https://clinicaltrials.gov/study/NCT05131022