Most therapies for B-cell malignancies are targeted therapy. By targeting BTK (bruton tyrosine kinase), a critical component of the B-cell receptor signaling pathway, several potent therapies have been developed. Most of these BTK inhibitors are covalent, which means that they bind to the active site of the enzyme in a covalent fashion and thus inhibit the enzyme’s enzymatic activity. While effective in several cases, resistance to these inhibitors occurs in relapsed or refractory disease, sometimes in a matter of months.
Tacabrutideg, also referred to as BGB-16673 or BGB16673, is a BTK-targeted protein degrader. BTK is an essential component of B-cell receptor signaling, which makes BTK an important target in the treatment of B-cell malignancies. While conventional BTK-inhibitors like ibrutinib are covalently attached to the BTK-tyrosine, BTK-degraders like Tacabrutideg utilize targeted protein degradation to remove BTK from B-cell malignancies. The drug is investigational and is not FDA-approved for the treatment of B-cell cancers.
The Clinical Need in Relapsed and Refractory Disease
Relapsed or refractory disease: A highly treatment-refractory patient population that has received multiple lines of therapy including covalent-inhibitor BTK products and BCL-2 inhibitors for B-cell malignancies, with limited subsequent therapeutic options to affect significant clinical benefit. The molecular basis of disease progression on prior therapy can include development of acquired, disease-specific molecular alterations or engagement of alternative pathways and cellular mechanisms to promote and sustain tumor-cell survival and proliferation.
In addition to continued efforts to develop additional inhibitors of the same target(s) of current therapies, of increasing interest are approaches that eliminate the same target(s) by different means of protein degradation that could offer alternative or additional therapeutic strategies for the treatment of relapsed or refractory disease.
Understanding Tacabrutideg
The term BTK-targeted protein degrader refers to the mechanism by which the molecule Tacabrutideg works. This is different from conventional, active-site-targeting, small-molecule inhibitors of BTK. Instead, Tacabrutideg is designed to use the cells’ normal protein degradation machinery to remove BTK from the malignant cells.
Clinical studies are evaluating whether BTK degradation may produce different clinical outcomes compared with BTK inhibition.
As reported by the FDA’s orphan-drug database, Tacabrutideg received Orphan Drug status for mantle cell lymphoma in 2023 and for follicular lymphoma in 2024; it has not yet been approved by the FDA for these indications.
Clinical Development Across B-Cell Malignancies
The Phase 1/2 study of Tacabrutideg is conducted in several B-cell malignancies. In addition to the previously mentioned MM, patients with marginal zone lymphoma, relapsed or refractory FL, relapsed or refractory DLBCL, relapsed or refractory SCT, WM, R- DLBCL and patients with CLL/SLL are treated with Tacabrutideg in dose escalation as well as in dose expansion phases to assess antitumor activity in addition to safety and to determine the optimal dose for each indicant.
Much of the work to be done to establish the efficacy of Tacabrutideg in the treatment of different B-cell cancers will rely on evidence gathered within individual clinical trials in specific diseases. As with any single molecular entity, activity in one B-cell malignancy does not necessarily translate to another.
Tacabrutideg After Covalent BTK Inhibitors
In a clinical context where BTK covalent inhibitors have already been applied in patients with relapsed or refractory B-cell malignancies, the investigation of BTK degradation via Tacabrutideg in a Phase 3 study compares Tacabrutideg to Pirtobrutinib in previously treated CLL/SLL patients. The primary objective of the study is to investigate safety and to assess efficacy of the two BTK targeting strategies in patients with relapsed or refractory CLL/SLL after covalent BTK inhibitor therapy.
This study will evaluate Tacabrutideg versus investigator choice (IDC) for the treatment of patients with previously treated CLL/SLL who are refractory to both a BTK inhibitor and a BCL-2 inhibitor. IDC for this study will be: idelalisib + rituximab, bendamustine + rituximab or venetoclax + rituximab retreatment.
These studies are particularly relevant given the substantial amount of prior use of targeted therapy in patients treated within these studies.
Combination Treatment Strategies
The BTK degradation approach may also be combined with other approaches to target cancer cells. A Phase 1/2 master study is currently recruiting patients with various types of relapsed or refractory B-cell malignancies to receive Tacabrutideg in combination with Sonrotoclax, Zanubrutinib, mosunetuzumab, and/or glofitamab. In this study, the investigator aims to assess safety, antitumor activity, pharmacokinetics, and pharmacodynamics in patients.
These combinations are examined to assess the potential of BTK degradation in combination with alternative modes of attack on malignant B-cells. The study of these combinations is largely investigational to assess the safety and efficacy of these treatment regimens.
Considerations for Healthcare Professionals
It is also important for healthcare professionals to remember that evidence regarding Tacabrutideg is continually being developed. Factors to consider when evaluating the utility of Tacabrutideg in individual patients include their specific type of B-cell malignancy, prior therapy, current disease status, inclusion criteria for available clinical trials, potential toxicities, and availability of trials.
It is important to note that even though Tacabrutideg has been granted breakthrough therapy designation, it has not received approval by the FDA to treat B-cell malignancies. Therefore, it must not be considered as a standard treatment for B-cell malignancies, and its current use is restricted to the frame of clinical trials in order to evaluate its potential benefit for the treatment of patients with relapsed or refractory B-cell malignancies.
Future Clinical Role
Ongoing studies will provide critical evidence of the long-term benefits and adverse effects of Tacabrutideg as well as of potential resistance pathways. Tacabrutideg is being evaluated in clinical studies to better understand its potential role in the treatment of B-cell malignancies.
Several additional important questions must be addressed to assess the long-term value of this novel approach to the treatment of B-cell malignancies, i.e. BTK degradation. Current clinical trials are designed to investigate the properties of tacabrutideg, either as a single agent or in combination with other drugs in patients with relapsed and/or refractory B-cell malignancies.
Conclusion
Tacabrutideg is another experimental approach to BTK targeting using the approach of targeted protein degradation (TPD) as opposed to conventional BTK inhibition. Clinical development is largely focused on use in patients with relapsed and/or refractory (RR) B-cell malignancies including those who have previously received BTK inhibitors as well as BCL-2 inhibitors.
Future studies may provide additional information regarding the safety and efficacy of Tacabrutideg. Until proven otherwise, Healthcare Professionals must continue to look to mature evidence from NCI-listed Phase 1/2 and Phase 3 studies in the treatment of relapsed and refractory B-cell malignancies to understand its appropriate use as an investigational therapeutic agent.
Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.
