ASH 2025 | Latest updates from the phase I NX-5948-301 trial of bexobrutideg in patients with R/R CLL

During the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, December 6–9, 2025, Orlando, US, the Lymphoma Hub was pleased to speak with Alexey Danilov, City of Hope Comprehensive Cancer Center, Duarte, US. We asked, What are the latest updates from the phase I NX-5948-301 trial of bexobrutideg in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)? 

Key points¹ 

• Bexobrutideg (NX-5948) is a novel Bruton’s tyrosine kinase (BTK) degrader that degrades BTK rather than inhibiting BTK function.
• The ongoing phase Ia/Ib NX-5948-301 trial (NCT05131022) is investigating the safety and efficacy of bexobrutideg in patients with R/R B-cell malignancies, including patients with R/R CLL.
• In the phase Ia dose-escalation cohort, patients with CLL were treated with bexobrutideg at doses ranging from 50 mg once daily to 600 mg once daily.
• In the phase Ib randomized cohort, patients with CLL were randomized to either bexobrutideg 200 mg or 600 mg once daily.
  • Based on the efficacy, safety, and pharmacokinetics data, bexobrutideg 600 mg was chosen for the ongoing phase Ib dose-expansion cohort.
• At the data cutoff of September 19, 2025, 126 patients with CLL had been enrolled (phase Ia, n = 48; phase Ib, n = 78).¹
  • Patients were heavily pre-treated, with a median of three and four prior lines of therapy in all patients and patients in the phase Ia cohort, respectively.
  • The majority of patients had prior exposure to BTK inhibitors or B-cell lymphoma-2 (BCL-2) inhibitors, with 59.5% and 81.3% of all patients and patients in the phase Ia cohort, respectively, exposed to both BTK inhibitor and BCL-2 inhibitor therapy.
  • Prior exposure to chimeric antigen receptor (CAR) T-cell therapy was reported in 7.1% of all patients and 6.3% of patients in the phase Ia cohort.
  • 66.7% and 72.9% of all patients and patients in the phase Ia cohort, respectively, had prior exposure to chemotherapy/chemoimmunotherapy.
  • The patients were characterized by high-risk genetics, with frequent occurrence of deletion 17p (del[17p]) and mutated BTK.
• Bexobrutideg was well tolerated, with the majority of adverse events (AEs) being Grade 1–2, and no dose-limiting toxicities were reported.
  • Neutropenia was the most common Grade 3 AE; however, there were no severe infections reported.
• Almost all patients experienced clinical benefit, with the majority of patients experiencing a reduction in lymph node size.
• In the phase Ia cohort, the overall response rate (ORR) was 83.0%; after a median follow-up of 16.6 months, the median progression-free survival (PFS) was 22.1 months.
  • Early data suggest that patients who received the 600 mg dose may have a longer PFS compared with patients who received the 200 mg dose. 

Danilov concludes by highlighting that bexobrutideg was well tolerated in heavily pre-treated patients with CLL, with high response rates and encouraging PFS outcomes.  

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