In a phase I, first-in-human trial of nearly 50 patients with relapsed or refractory B-cell malignancies, the orally administered, small molecule degrader bexobrutideg (NX-5948) was reported to be well tolerated, including in those with a longer duration of treatment and higher doses. Clinical activity with this agent was shown in a heavily pretreated population with advanced chronic lymphocytic leukemia (CLL); the objective response rate for the phase Ia cohort was 80.9%, with a median time to first response of 1.9 months. These updated early-phase study results were presented by Nirav N. Shah, MD, MSHP, Professor of Medicine and Director of the BMT & Cellular Therapy Program at the Medical College of Wisconsin, on behalf of colleagues, at the 2025 Society of Hematologic Oncology (SOHO) Annual Meeting.¹Enrollment is ongoing for the phase Ib dose-expansion part of the study (200-mg and 600-mg cohorts).

There is a deepening of response with prolonged duration of therapy with bexobrutideg, and this is happening at all dose levels.

— NIRAV N. SHAH, MD, MSHP

Tweet this quote

Dr. Shah briefly explained how Bruton’s tyrosine kinase (BTK) degraders may address an unmet need in the CLL treatment landscape. It is well known that the current standard of care in CLL centers on the use of BTK and BCL2 inhibitors, but many patients develop resistance mutations to covalent and noncovalent BTK inhibitors. Novel BTK degraders such as bexobrutideg may overcome treatment-emergent resistance mutations and disrupt BTK scaffolding, he noted. In essence, this novel therapy induces removal of wild-type and mutant BTK through ubiquitination by cereblon E3 ligase complex and subsequent proteasomal degradation.

“This pathway of degradation is a very exciting modality to target BTK in a different fashion than the inhibitors we have been using to date,” Dr. Shah stated. “In time, we will see if these agents can actually prevent some of the mutations we see with continuous BTK inhibitors.”

Study Details

This trial consisted of parallel 3 + 3 dose-escalation (Ia) and dose-expansion (Ib) cohorts. As of January 2025, phase Ia was fully enrolled, with 48 patients who had CLL or small lymphocytic lymphoma. The median patient age was 68.5 (range, 35–88 years), and approximately two-thirds were male.

All study patients had to have at least two prior lines of therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. A total of 97.9% had received treatment with a covalent BTK inhibitor, 81.3% had received the combination of a BTK inhibitor and a BCL2 inhibitor, and 72.9% had received chemotherapy or chemoimmunotherapy. Some patients had been treated with a PI3K inhibitor (29.2%) and chimeric antigen receptor T-cell therapy (6.3%). In addition, baseline BTK mutations such as C481S and T474F were identified in 10 patients and 5 patients, respectively.

“What is really exciting about this class of degraders is that regardless of the type of mutation present in the baseline population, you see a deep and rapid degradation of the BTK,” explained Dr. Shah.

Six dose levels of bexobrutideg daily were tested: 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). The primary objectives were safety or tolerability and identification of a recommended phase II dose. The secondary objectives included pharmacokinetics/pharmacodynamic analyses and preliminary efficacy.

Key Results

In terms of safety in the phase Ia part of the study, treatment with bexobrutideg across all doses was reported to be well tolerated, with a median duration of treatment of 7 months. No dose-limiting toxicities were observed, with one case of treatment discontinuation (grade 2 hot flushes). The most common treatment-emergent adverse events were purpura/contusion (45.8%, no grade ≥ 3); fatigue (31.3%, no grade ≥ 3); diarrhea (31.3%, with 2 cases grade ≥ 3); neutropenia (29.2%, with 11 cases grade ≥ 3); rash (27.1%, with 1 case grade ≥ 3); and petechiae (25.0%, no grade ≥ 3). No cases of systemic fungal infections nor new-onset atrial fibrillation were reported.

In terms of early efficacy (with a median follow-up of 9 months), the objective response rate in the 47 response-evaluable patients was 80.9% (95% confidence interval [CI] = 66.7%–90.9%). There was 1 complete response, 37 partial responses, and 7 cases of stable disease. “Almost every patient had some degree of clinical benefit,” stated Dr. Shah, “and that included those patients who had CNS involvement with CLL as well.”

In addition, 18 patients now have a duration of response of more than 12 months; of these patients, 17 remain on study. “There is a deepening of response with prolonged duration of therapy with bexobrutideg,” he added, “and this is happening at all dose levels.”

One patient, a 71-year-old woman with no BTK mutations, experienced conversion from a partial response to a complete response after 26 months of treatment. Dr. Shah noted this illustrates that some evolution of complete response may occur over time. “We need more patients to be further out to see if this is a common finding, which would be excellent news, as complete responses are difficult with BTK inhibitors alone,” Dr. Shah concluded.

DISCLOSURE: This study is sponsored by Nurix Therapeutics. Dr. Shah has served as an advisor or consultant to Nurix, Gilead-Kite, BMS-Juno, Miltenyi Biomedicine, Lilly Oncology, Incyte, AbbVie, Cargo, BeOne Medicines (formerly BeiGene), Kite Pharma, Allogene Therapeutics, AstraZeneca, BMS, Ipsen, Genentech, and Galapagos; has received research funding from Lilly Oncology, Genentech, and Miltenyi Biomedicine; has received travel support from Lilly Oncology and Miltenyi Biomedicine; has served on a scientific advisory board for Tundra Therapeutics; and is a Scholar in Clinical Research for Blood Cancer United.

REFERENCE

1. Omer Z, Danilow A, Forconi F, et al: Bexobrutideg (N-5948), a novel Bruton’s tyrosine kinase degrader, demonstrates rapid and durable clinical responses in relapsed/refractory chronic lymphocytic leukemia: Updated findings from an ongoing phase 1a study. 2025 SOHO Annual Meeting. Abstract CLL-563. Presented September 4, 2025.

EXPERT POINT OF VIEW

Session Chair of chronic lymphocytic leukemia (CLL) at the 2025 Society of Hematologic Oncology (SOHO) Annual Meeting, John Seymour, MBBS, FRACP, PhD, shared these comments on the early-phase study findings with the novel Bruton’s tyrosine kinase (BTK) degrader bexobrutideg in relapsed or refractory CLL. Dr. Seymour is Director of the Haematology Department of the Royal Melbourne Hospital, Peter MacCallum Cancer Centre and the University of Melbourne, Australia.

John Seymour, MBBS, FRACP, PhD

“This abstract was one of the highlights of the session for reasons beyond the strength of these early data for this specific compound,” Dr. Seymour wrote in e-mail correspondence with The ASCO Post. “More broadly, in many of these patients, the effectiveness of a third compound in their treatment history targeting BTK reaffirmed the validity and robustness of the B-cell receptor pathway/BTK as a critical dependency for CLL. Also, the increasingly impressive accumulating data for this BTK degrader (and others using the E3-ligase ubiquitination pathway) suggest enormous promise for that mechanism to address both protein targets, where resistance has emerged to more conventional mechanistic inhibitors. It also represents a potential means to target hitherto ‘undruggable’ molecules such as BCL6, MYC, and RAS.”

DISCLOSURE: Dr. Seymour has received honoraria from AbbVie, AstraZeneca, BeOne Medicines (formerly BeiGene), BMS, Gilead Sciences, Janssen, Loxo, and Roche; has served as a consultant to BMS and TG Therapeutics; and has received research funding from AbbVie, BMS, Janssen, Loxo, and Roche.