First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101)
Abstract
Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (P…
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NX-5948, BGB-16673 and ABBV-101 are other BTK degraders in clinical development that have shown preliminary activity in ongoing studies.
“Other BTK degraders in clinical development include NX-5948, BGB-16673 and ABBV-101, which have shown preliminary activity in ongoing studies(91–93).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [91]
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Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
Gruessner, C., Wiestner, A., & Sun, C. (2025) · Leukemia & Lymphoma · doi:10.1080/10428194.2025.2466101 · Cited by 6 · see citing works
“Other BtK degraders in clinical development include NX-5948, BGB-16673 and ABBv-101, which have shown preliminary activity in ongoing studies [90–92].”
- Authors
- Seymour, J. F., Cheah, C. Y., Parrondo, R., Thompson, M. C., Stevens, D. A., Lasica, M., Wang, M. L., Kumar, A., Trotman, J., Alwan, M., Ding, W., By, K., Tariq, B., Chen, X., Fabre, S., Paik, J., Agarwal, A., & Tam, C. S.
- Affiliations
- The Royal Melbourne Hospital (AU)
- The University of Western Australia (AU)
- Mayo Clinic in Florida (US)
- Memorial Sloan Kettering Cancer Center (US)
- 7Norton Cancer Institute, Louisville, KY
- St Vincent's Hospital Melbourne (AU)
- The University of Texas MD Anderson Cancer Center (US)
- University of Arizona (US)
- The University of Sydney (AU)
- 12Perth Blood Institute, West Perth, Australia
- Mayo Clinic (US)
- 14BeiGene USA, Inc, San Mateo, CA
- 15BeiGene (Shanghai) Co, Ltd, Shanghai, China
- 16BeiGene, San Mateo, CA
- The Alfred Hospital (AU)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2023-11-02
- Volume
- 142
- Issue
- Supplement 1
- Pages
- 4401-4401
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W4389231314
- Cited by
- 71
- References
- 0
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 26
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- BTK degraders, Bruton's tyrosine kinase, relapsed or refractory B-cell malignancies, chronic lymphocytic leukemia, Waldenström macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, BTK inhibitor resistance, E3 ubiquitin ligase, dose-limiting toxicity, maximum tolerated dose
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