Tacabrutideg (BGB-16673) is an investigational, orally available BTK-targeting chimeric degradation activation compound (CDAC) designed to degrade both wild-type and mutant BTK, including resistance-associated variants that drive progression after prior BTK inhibitor therapy. Originating from BeOne’s CDAC platform, it offers a differentiated mechanism by inducing targeted protein degradation rather than inhibition, addressing a key driver of resistance in relapsed/refractory B-cell malignancies.

The FDA has granted Fast Track Designation for R/R CLL/SLL and R/R mantle cell lymphoma (MCL), while the EMA has granted PRIME designation in previously treated Waldenström’s macroglobulinemia, highlighting its potential in high-unmet-need settings. The ongoing Phase I/II CaDAnCe-101 trial is evaluating BGB-16673 in heavily pretreated B-cell malignancies, including post-BTK and post-BCL2 inhibitor populations, with early signals of durable clinical activity. A Phase II BTK CDAC study in R/R CLL is planned, with potential accelerated approval submission anticipated in H2 2026.

Key Efficacy Highlights:

 

Key Safety Highlights:

• Any-grade TEAEs: 97.0%; Most common (≥25%): fatigue (37.3%), contusion (32.8%), diarrhea (29.9%), neutropenia/decreased neutrophil count (29.9%)

• Grade ≥3 TEAEs: 61.2%; Most common (≥5%): infections (34.3%), neutropenia/decreased neutrophil count (25.4%), thrombocytopenia/decreased platelet count (7.5%)

• Dose reductions: 13.4% (n=9)

• Treatment discontinuation: 17.9% (n=12), including 6.0% due to treatment-related AEs (subdural hemorrhage, peripheral swelling and ecchymosis, maculopapular rash, disseminated aspergillosis)

• TEAEs leading to death: 7.5%, all infection-related (one in the context of progressive disease)

KOL insights

“Tacabrutideg has a potential next-generation role in relapsed/refractory CLL by enabling BTK degradation, which may help overcome resistance after both BTK and BCL2 inhibitor failure. The durable responses observed in high-risk, mutation-driven disease highlight its promise as a meaningful option in a setting with limited effective therapies.” – Expert Opinion

“A major advantage of BTK degraders is their ability to eliminate BTK independent of mutation status, effectively targeting both wild-type and mutant protein forms. This is particularly relevant in the relapsed setting, where a substantial proportion of patients progressing on covalent BTK inhibitors harbor resistance-associated BTK mutations. The capacity to maintain activity across these mutant clones is viewed as both reassuring and potentially clinically meaningful in overcoming acquired resistance.”– Expert Opinion

Conclusion: 

CLL/SLL is a slow-growing but ultimately incurable B-cell malignancy, with disease driven by abnormal proliferation and survival of clonal B lymphocytes that accumulate in blood, bone marrow, and lymphoid tissues. It is typically diagnosed in older adults, with a median age at diagnosis of around 72 years. In the UK, approximately ~4,700 new cases are diagnosed annually. While BTK and BCL2 inhibitors have fundamentally transformed the treatment paradigm and significantly improved survival outcomes, they have also led to a growing subgroup of patients who relapse after both therapies and face limited effective options. In this setting, tacabrutideg (BGB-16673), a novel BTK-targeting chimeric degradation activation compound (CDAC), represents a next-generation strategy designed to overcome resistance by degrading both wild-type and mutant BTK, including variants that drive post-BTK inhibitor progression. The Phase I/II CaDAnCe-101 study demonstrates high and durable responses in heavily pretreated, double-exposed patients, highlighting BTK degradation as a promising next-generation approach to address a critical unmet need for deeper and more sustained disease control beyond current targeted therapies.