Bexobrutideg Demonstrates High Efficacy and Safety in Waldenström Macroglobulinemia

In an exciting development for the treatment of relapsed and refractory Waldenström macroglobulinemia, the novel small molecule Bruton’s tyrosine kinase (BTK) degrader, bexobrutideg (NX-5948), has exhibited a remarkable objective response rate (ORR) of 84.2%, according to findings presented at the 2025 European Hematology Association Congress. The phase 1a/b study, which enrolled 22 patients with prior treatment history, underscored both the tolerability and potential efficacy of bexobrutideg in a patient population that has limited treatment options.

The study, led by Dr. Dima El-Sharkawi, MBBS, PhD, MRCP, FRCPath, a consultant hematologist at the Royal Marsden Hospital in London, focused on individuals who had previously undergone at least two lines of therapy, including a BTK inhibitor. At a median follow-up of 3.7 months, the study reported that while no complete responses were documented, the results included very good partial responses (10.5%), partial responses (57.9%), and minor responses (15.8%). Notably, three patients experienced stable disease, showcasing the drug's potential in a challenging treatment landscape.

"Bexobrutideg demonstrated a high ORR of 84.2%," said Dr. El-Sharkawi during his poster presentation, emphasizing the drug’s clinical activity in patients with baseline mutations and multiple previous therapies.

Bexobrutideg's promising safety profile is equally noteworthy. With no dose-limiting toxicities or grade 5 adverse effects reported, the most common treatment-emergent adverse events included petechiae (27.3%), diarrhea (22.7%), and neutropenia (18.2%). Despite the occurrence of these side effects, the absence of severe complications suggests a favorable risk-benefit ratio for patients.

The drug has garnered significant regulatory attention, receiving both fast track and orphan drug designations from the U.S. Food and Drug Administration (FDA). This regulatory recognition reflects the drug's potential in addressing unmet needs in the treatment of Waldenström macroglobulinemia, a rare and challenging hematologic malignancy.

The NX-5948-301 study employed a 3+3 dose-escalation followed by a dose-expansion design, with patients receiving varying dosages of bexobrutideg, including 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, and 600 mg once daily. The trial also includes an expansion cohort for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who have received prior treatments, aiming to further elucidate the efficacy and safety across different malignancies.

Looking ahead, the implications of bexobrutideg's success could be far-reaching. As highlighted by Dr. El-Sharkawi, the promising results call for further investigation into the drug's long-term effectiveness and safety. The ongoing studies will not only refine treatment protocols but also enhance understanding of its pharmacokinetic and pharmacodynamic profiles, potentially paving the way for broader applications in other malignancies.

In summary, the phase 1a/b study of bexobrutideg presents a hopeful narrative for patients with relapsed/refractory Waldenström macroglobulinemia, offering a potential new avenue of treatment that may improve outcomes in this challenging patient population. Further studies will be critical to validate these findings and determine the role of bexobrutideg in the future treatment landscape of hematologic malignancies.