Covalent BTK inhibitors are used in the treatment of certain B-cell malignancies and have demonstrated clinical activity in multiple studies. Many of these resistant malignancies are refractory to most standard treatments and represent significant clinical challenges. To combat these obstacles, researchers are investigating alternative methods of targeting BTK.
The Changing Role of BTK-Directed Therapy
However, covalent BTK inhibitors have limitations, including the potential for acquired resistance. BTK mutations, including C481S, confer resistance to covalent BTK inhibitors and have been found in many patients with CLL and lymphoma treated with these agents. To overcome these limitations of covalent BTK inhibitors, alternative strategies for targeting BTK have been developed.
In contrast, non-covalent BTK inhibitors are under development. On the other hand, targeted protein degradation (TPD) aims to promote the degradation of the BTK protein by the cells’ protein degradation machinery. Given that resistant malignancies often retain function of BTK, even in the presence of BTK inhibitors, there is interest in developing novel BTK-targeted therapies that function via different mechanisms, particularly for tumors that are resistant to conventional BTK inhibitors.
Understanding Tacabrutideg
Tacabrutideg (BGB-16673) is an investigational BTK-targeted protein degrader. As opposed to conventional inhibitors of BTK which predominantly inhibit the activity of the protein, BGB-16673 induces the degradation of BTK protein. An early research publication described the agent as a BTK degrader and reported robust BTK degradation in preclinical models as well as in clinical-dose-range studies published in the British Journal of Pharmacology.
In terms of the pharmacological approach of targeted BTK degradation, versus targeted inhibition of the enzyme, the proteins in the tumor and leukemia cells and in normal tissues can be unique in structure in terms of amino acid substitutions. An early study had shown that non-covalent BTK inhibitors (albeit of low potency) retained activity against forms of BTK with specific mutations that confer resistance to covalent (inhibitory) BTK inhibitors, such as BGB-580. The clinical relevance of these findings remains under investigation and requires further evaluation in clinical studies.
Relevance in Relapsed or Refractory B-Cell Malignancies
Most patients with B-cell malignancies relapse within several years and are defined as having refractory disease. Prior treatment with other targeted therapies, including other BTK inhibitors, forms the basis for the treatment choice of relapsed/refractory patients. And, after a period, most of these malignancies also acquire key additional molecular changes that are then critical for continued disease progression.
Different treatment mechanisms are being studied across various disease settings. Early clinical studies have been conducted to investigate the safety, pharmacodynamics and antitumor activity of BGB-16673, a novel BTK degrader, in relapsed or refractory CLL/SLL and WM patients.
When evaluating the emerging BTK degrader agent, it is also essential to appreciate that data from early-phase studies must be viewed within the context of ongoing clinical development. Furthermore, even compelling early-phase data does not immediately translate to a new treatment becoming a ‘standard of care’.
Resistance Remains an Important Consideration
Resistance to BTK degradation will not necessarily be averted. As described for conventional BTK inhibitors, acquired resistance can occur by various distinct mechanisms, some of which are already identified for the BTK degrader Tacabrutideg. While some resistance mechanisms are thought to be abrogated by degradation of BTK, others are not.
An example of clinical resistance, where a single mutation in the BTK kinase domain confers resistance to a BTK degrader in CLL, has been reported and is under investigation (A428D). Further clinical and molecular studies are required to investigate the potential for resistance to be developed to Tacabrutideg in patients with B-cell malignancies.
Importantly, there are limits to how a protein degradation approach can be expected to confer advantage over other targeted protein degradation strategies or conventional protein inhibition. Most critically, because most kinases are inhibited by their targeted degradation, understanding the specific disease biology, prior treatment, and other important clinical factors will be crucial for determining whether a resistance mutation to a protein degradation-based BTK inhibitor will confer different clinical outcomes.
What Healthcare Professionals Should Monitor
Healthcare professionals can monitor several parameters for drugs in this emerging class of BTK-targeted protein degraders. These would include duration of response; profiles of adverse events; pharmacodynamic effects of BTK degradation; and mechanisms of resistance to the new agent. In addition, it is important to have data in patients previously treated with both covalent and non-covalent BTK inhibitors.
In the context of CLL/SLL, it will be important to establish the optimal positioning of these agents within treatment sequences for this indication, i.e. as initial therapy versus as salvage after failure of prior therapies. In the future clinical trials will be how Tacabrutideg and other novel agents are proven to be safe and effective in addition to defining their place in treatment algorithms for patients with CLL/SLL.
The Broader Future of B-Cell Malignancy Care
The emerging class of protein degraders for the treatment of hematologic malignancies is reviewed with an emphasis on the variety of approaches to eradicate cancer-driving proteins by proteasomal degradation, using targeted therapies as a conceptual framework to address mechanisms of resistance to conventional cancer therapies.
Tacabrutideg is an investigational agent within an emerging class of therapies currently under clinical evaluation. Information regarding this new drug as it matures and becomes available will be important for the US healthcare professional to evaluate in terms of safety, efficacy, resistance, indication and in combination with other current targeted therapies for the treatment of B-cell malignancies.
Conclusion
The early data and ongoing research examining the effects of Tacabrutideg provide a basis for its continued investigation, but recognition of emerging resistance determinants and their clinical impact will necessitate close monitoring of clinical trials, publications and other information relating to this therapeutic. clinicians should look for forthcoming evidence as well as for current and future trials on this emerging class of therapeutics for B-Cell Malignancy.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.
Lynn Martelli is an editor at Readability. She received her MFA in Creative Writing from Antioch University and has worked as an editor for over 10 years. Lynn has edited a wide variety of books, including fiction, non-fiction, memoirs, and more. In her free time, Lynn enjoys reading, writing, and spending time with her family and friends.
