Bexobrutideg Is Tolerable and Yields High Response Rates in Relapsed/Refractory Waldenström Macroglobulinemia

Waldenström Macroglobulinemia | Image credit:

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The novel small molecule BTK degrader bexobrutideg (NX-5948) demonstrated significant clinical activity with a tolerable safety profile in patients with relapsed/refractory Waldenström macroglobulinemia, according to data from the phase 1a/b NX-5948-301 study (NCT05131022) presented during the 2025 European Hematology Association Congress.1

At a median follow-up of 3.7 months (range, 1.9-18.9), response-evaluable patients who received bexobrutideg at any dose (n = 19) achieved an objective response rate (ORR) of 84.2%. No complete responses were reported, however patients achieved very good partial responses (10.5%), partial responses (57.9%), and minor responses (15.8%). There were also 3 patients who experienced stable disease.

At the March 12, 2025, data cutoff, the median duration of response was not reached (NR; 95% CI, 2.89-NR) in the overall population (n = 22). Two patients reached over 1 year of follow-up.

“Bexobrutideg demonstrated a high ORR of 84.2%,” Dima El-Sharkawi, MBBS, PhD, MRCP, FRCPath, said in a poster presentation of the findings. “Clinical activity was observed in patients with baseline mutations and multiple previous lines of therapy.”

El-Sharkawi is a consultant hematologist at the Royal Marsden Hospital in London, United Kingdom.

In December 2024, bexobrutideg received fast track designation from the FDA for the treatment of patients with relapsed/refractory Waldenström macroglobulinemia who received at least 2 prior lines of therapy, including a BTK inhibitor.2 In March 2025, the agent received orphan drug designation from the FDA in patients with Waldenström macroglobulinemia.3

NX-5948-301 Design, Objectives, and Baseline Characteristics

NX-5948-301 enrolled patients with relapsed/refractory B-cell malignancies, including Waldenström macroglobulinemia.1 Key eligibility criteria included prior treatment with a BTK inhibitor and an ECOG performance status of 0 or 1. Patients with central nervous system involvement were permitted to be enrolled.

The trial employed a 3+3 dose-escalation then dose-expansion design. During the phase 1a dose-escalation portion, patients with Waldenström macroglobulinemia received bexobrutideg at a dose of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, or 600 mg once daily. NX-5948-301 also includes a fully enrolled phase 1b expansion cohort where patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who received a prior BTK inhibitor and BCL2 inhibitor will be randomly assigned to receive bexobrutideg at a dose of 200 mg or 600 mg. There are also ongoing expansion cohorts for patients with Waldenström macroglobulinemia, marginal zone lymphoma, and follicular lymphoma.

The objectives of the trial were safety and tolerability, establishment of a maximum tolerated dose, and identification of a recommended phase 2 dose. Secondary objectives included characterization of the pharmacokinetic/pharmacodynamic profile and assessment of preliminary efficacy per 6th International Workshop on Waldenström Macroglobulinemia criteria.

At baseline, the median age was 72.5 years (range, 58-86). Most patients were male (81.8%), had an ECOG performance status of 1 (63.6%), and had MYD88-mutated disease (68.2%). The median number of prior lines of therapy was 3 (range, 2-5). All patients received a prior BTK inhibitor; patients were also previously treated with noncovalent BTK inhibitors (18.2%), BCL2 inhibitors (4.5%), both BTK and BCL2 inhibitors (4.5%), and/or chemotherapy/chemoimmunotherapy (95.5%).

In the analysis shared during the poster presentation, patients received bexobrutideg at a dose of 200 mg (n = 1), 300 mg (n = 3), 450 mg (n = 2), or 600 mg (n = 16).

Safety Findings

In terms of safety, there were no dose-limiting toxicities or grade 5 adverse effects (AEs). Treatment-emergent AEs (TEAEs) resulting in drug discontinuation and treatment-related serious AEs (SAEs) were reported in 2 patients each.

The most common any-grade TEAEs included petechiae (27.3%), diarrhea (22.7%), purpura/contusion (18.2%), neutropenia (18.2%), thrombocytopenia (18.2%), and upper respiratory tract infection (18.2%). Grade 3 or higher TEAEs consisted of anemia (9.1%), neutropenia (4.5%), thrombocytopenia (4.5%), fall (4.5%), lower respiratory tract infection (4.5%), influenza (4.5%), influenzal pneumonia (4.5%), sepsis (4.5%), and hypertension (4.5%). SAEs included fall (4.5%), influenza (4.5%), influenzal pneumonia (4.5%), sepsis (4.5%), and subdural hematoma (4.5%).

“Bexobrutideg was well tolerated, with a safety profile [that was] consistent between the Waldenström macroglobulinemia and overall populations that were previously reported,” El-Sharkawi said.

Disclosures: None were listed.

References

1. El-Sharkawi D, Lewis D, Pulles A, et al. Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase degrader, shows high clinical activity and tolerable safety in an ongoing phase 1a/b study in patients with Waldenström macroglobulinemia. Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1883.
2. Nurix Therapeutics receives U.S. FDA fast track designation for NX-5948 for the treatment of relapsed or refractory Waldenstrom’s macroglobulinemia. News release. Nurix Therapeutics. December 19, 2024. Accessed June 17, 2025. https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-receives-us-fda-fast-track-designation-nx-0
3. Nurix announces U.S. FDA orphan drug designation granted to bexobrutideg (NX-5948) for the treatment of Waldenström macroglobulinemia. News release. Nurix Therapeutics. March 17, 2025. Accessed June 17, 2025. https://ir.nurixtx.com/news-releases/news-release-details/nurix-announces-us-fda-orphan-drug-designation-granted