Bexobrutideg Shows Early Promise in BTK- and BCL2-Exposed, Relapsed/Refractory CLL

Bexobrutideg (NX-5948) elicited responses that proved durable with a low rate of grade 3 or greater treatment-emergent adverse effects (TEAEs) in patients with heavily pretreated, relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to updated data from the CLL cohort of the phase 1a portion of the NX-5948-301 trial (NCT05131022).1

Findings presented during the 2025 SOHO Annual Meeting demonstrated that with a median follow-up of 9.0 months (range, 1.6-26.1), the objective response rate in evaluable patients (n = 47) was 80.9% (95% CI, 66.7%-90.9%). Best responses included complete response (2.1%), partial response ([PR] 78.7%), and stable disease (14.9%). Two patients (4.3%) had progressive disease. Clinical activity was also evident irrespective of TP53 or PLCG2 mutation status, type of covalent or noncovalent BTK inhibitor resistance mutation, or central nervous system (CNS) involvement.

Durable responses were also seen regardless of prior therapy (n = 48). The median time to first response was 1.9 months (range, 1.6-11.1) and the median duration of response was not reached ([NR] 95% CI, 10.6-NR). Twenty-one patients received escalated doses of bexobrutideg and 18 remained on treatment for more than 1 year, 17 of whom remain on study. Bexobrutideg also reduced lesion sizes according to changes in the sum of product diameters from baseline.

“In the fully enrolled phase 1a CLL portion of the NX-5948-301 study, as of the 12 March 2025 data cut, bexobrutideg was well tolerated, consistent with the overall study population and previous disclosures,” lead study author Nirav N. Shah, MD, an associate professor of medicine at the Medical College of Wisconsin in Milwaukee, and coauthors, wrote in the poster. “Bexobrutideg [also] showed clinical activity in a population of heavily pretreated patients with advanced CLL.”

What Is the Unmet Clinical Need Bexobrutideg Could Help Fill in CLL/SLL?

BTK and BCL2 inhibition are two of the primary therapeutic avenues for CLL treatment. Despite this, more than half of patients will develop covalent and noncovalent BTK inhibitor resistance mechanisms, rendering the therapy ineffective, resulting in a temporary window before patients become single or double refractory to BTK/BCL2 inhibition. Bexobrutideg is a novel, small molecule that degrades wild-type and mutant forms of BTK by ubiquitination via the cereblon E3 ligase complex and subsequent proteasomes, affording an additional therapeutic option for patients with treatment-emergent BTK inhibitor resistance mutations.

In January 2024, the FDA granted fast track designation to bexobrutideg for the treatment of patients with relapsed/refractory CLL/SLL following at least 2 lines of therapy, including a BTK and BCL2 inhibitor.2

Earlier findings from the CLL cohort of the trial presented at the 2023 ASH Annual Meeting & Exposition indicated that among 6 of 7 patients who had received doses ranging from 50 mg to 200 mg, 3 PRs had been ongoing as of the October 17, 2023, data cutoff.

What Do I Need to Know About the Ongoing NX-5948-301 Trial?

NX-5948-301 is a phase 1 trial evaluating the efficacy and safety of bexobrutideg in patients with relapsed/refractory B-cell malignancies, including CLL and non-Hodgkin lymphoma in parallel 3+3 dose-escalation and dose-expansion cohorts.1 To be eligible for any cohort, patients must be at least 18 years of age and have relapsed or refractory disease following at least 2 prior lines of therapy with an ECOG performance status of 0 or 1.

The primary objective of phase 1 is to determine the safety and tolerability of the agent, as well as the recommended phase 2 dose. Secondary objectives include characterizing the pharmacokinetic/pharmacodynamic profile of the agent and gauging initial efficacy according to International Working Group CLL criteria.

Within the phase 1a portion of the CLL cohort, 6 dose levels were explored: 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, and 600 mg all given once daily. In the phase 1b portion, patients will receive 200 mg and 600 mg of bexobrutideg once daily. Additional phase 1b cohorts will evaluate the agent in patients with non–BTK C481S mutations with prior BTK and BCL2 exposure; prior noncovalent BTK exposure only; TP53-mutant or 17p deleted disease in the second line following prior BTK inhibition only; second- or later-line disease with prior BTK inhibition only; BTK-naive disease; warm antibody autoimmune hemolytic anemia and prior BTK inhibition; and CNS involvement with prior BTK inhibition.

At the data cutoff date of March 12, 2025, 48 patients with CLL/SLL had been enrolled in phase 1a and treated with the agent at doses of 50 mg (n = 3), 100 mg (n = 5), 200 mg (n = 9), 300 mg (n = 8), 450 mg (n = 7), and 600 mg (n = 16). A total of 32 patients remain on treatment. Reasons for discontinuation included radiographic progression (n = 7), clinical progression (n = 3), death (n = 2), an adverse effect ([AE] n = 1), physician decision (n = 1), receipt of a prohibited medication or procedure (n = 1), and patient withdrawn consent (n = 1).

Does the Patient Population Reflect My Clinical Practice?

The median patient age was 68.5 years (range, 35-88) and 66.7% of patients were male. The minority were Hispanic or Latino (6.3%), Black or African American (6.3%), or other (2.1%) relative to White patients (87.5%). ECOG performance status was 0 (39.6%) or 1 (60.4%) and 10.4% of patients had CNS involvement. The median number of prior lines of therapy was 4 (range, 2-12). Prior treatments included BTK inhibitors (97.9%; covalent, 97.9%; noncovalent, 27.1%), BCL2 inhibitors (83.3%), BTK and BCL2 inhibitors (81.3%), CAR T-cell therapy (6.3%), bispecific antibodies (6.3%), PI3K inhibitors (29.2%), and chemotherapy or chemoimmunotherapy (72.9%). Represented mutational profiles included BTK (38.3%), TP53 (44.7%), PLCy2 (14.9%), and BCL2 (12.8%).

“A high number of patients had BTK, PLCG2, and BCL2 mutations, high-risk molecular features, and CNS involvement,” Shah stated. “No patient profile was associated with intrinsic resistance to bexobrutideg,”

How Tolerable Is Bexobrutideg?

With respect to safety, Shah noted, “There was one TEAE resulting in drug discontinuation, no dose-limiting toxicities, and no new onset atrial fibrillation/flutter.”

TEAEs that occurred in at least 10% of patients (n = 48) included purpura/contusion (any grade, 45.8%), diarrhea (any grade, 31.3%; grade ≥3, 4.2%), fatigue (any grade, 31.3%), neutropenia (any grade, 29.2%; grade ≥3, 22.9%), rash (any grade, 27.1%; grade ≥3, 2.1%; serious AEs, 2.1%), petechiae (any grade, 25.0%), headache (any grade, 25.0%), thrombocytopenia (any grade, 22.9%; grade ≥3, 2.1%), anemia (any grade, 18.8%; grade ≥3, 4.2%), COVID-19 (any grade, 18.8%), peripheral edema (any grade, 18.8%), cough (any grade, 16.7%), lower respiratory tract infection (any grade, 14.6%; grade ≥3, 2.1%; serious AEs, 2.1%), nausea (any grade, 14.6%), pneumonia (any grade, 12.5%; grade ≥3, 4.2%; serious AEs, 4.2%), arthralgia (any grade, 12.5%), upper respiratory tract infection (any grade, 10.4%), vomiting (any grade, 10.4%; grade ≥3, 2.1%), and respiratory syncytial virus infection (any grade, 4.2%; grade ≥3, 2.1%; serious AEs, 4.2%).

Enrollment is ongoing in additional cohorts of the phase 1b trial, and launch of the pivotal trial(s) regarding bexobrutideg is expected before the years end.

Disclosures: No disclosures were included for Shah.

References

1. Shah NN, Omer Z, Danilov A, et al. Bexobrutideg (NX-5948), a novel Bruton’s Tyrosine Kinase (BTK) degrader, demonstrates rapid and durable clinical responses in relapsed/refractory CLL: updated findings from an ongoing phase 1a study. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract CLL-563.
2. Nurix Therapeutics receives U.S. FDA fast track designation for NX-5948 for the treatment of relapsed or refractory CLL and SLL. News release. Nurix Therapeutics, Inc. January 16, 2024. Accessed September 10, 2025. https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-receives-us-fda-fast-track-designation-nx