December 10, 2023
By Dibash Kumar Das, PhD
In the pursuit of more effective therapies for B-cell malignancies, a new Phase Ib study is underway, exploring the potential of AS-1763, a promising oral, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. The progress of the study was presented at the 65th ASH Annual Meeting and Exposition held December 9-12, 2023 (Abstract 3288).
Unlike conventional covalent BTK inhibitors, such as ibrutinib, AS-1763 demonstrates potent selectivity and circumvents issues of acquired resistance, offering a beacon of hope for patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphoma (NHL).
AS-1763's journey began with preclinical studies showcasing its efficacy against a broad spectrum of BTK mutations, including the challenging C481 mutation. This non-covalent inhibitor holds the potential to overcome the limitations posed by current treatments, opening new avenues for patients facing relapsed or refractory B-cell malignancies. With encouraging results from a Phase I single-ascending dose study in healthy volunteers, AS-1763 emerged as a well-tolerated and safe option, setting the stage for its evaluation in a clinical setting.
The ongoing Phase Ib study embraces an open-label, multi-center approach, enrolling patients with advanced CLL/SLL and other B-cell NHLs who have exhausted or cannot tolerate at least two prior lines of systemic therapy. Notably, patients with prior exposure to covalent BTK inhibitors are included, while those with prior non-covalent BTK inhibitor use are excluded. The study comprises dose-escalation and expansion parts with the primary objective of determining the maximum tolerated dose and dose-limiting toxicity.
For the dose-escalation part, the study focuses on defining the maximum tolerated dose and assessing key secondary endpoints, including safety, tolerability, and pharmacokinetics. The dose-expansion part aims to evaluate preliminary anti-tumor activity with the Safety Monitoring Committee playing a pivotal role in determining the overall response rate.
Key secondary objectives encompass an extensive exploration of safety profiles, pharmacokinetic properties, and anti-tumor activity based on investigator assessments. Exploratory objectives include the evaluation of minimal residual disease negativity and the characterization of patient subsets based on BTK and phospholipase C gamma 2 (PLCG2) mutation status.
To learn more about the ongoing study, Oncology Times reached out to lead author, Nitin Jain, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.
Oncology Times: What are the key differences between covalent and non-covalent BTK inhibitors? How might these differences impact their effectiveness in patients with CLL/SLL and other B-cell NHLs?
Jain: “Covalent BTK inhibitors bind to C481 residue of the BTK protein. Currently, three covalent BTK inhibitors are FDA-approved, namely ibrutinib, acalabrutinib, and zanubrutinib. They have shown improved clinical activity in CLL in randomized clinical trials compared to chemoimmunotherapy. One of the major mechanisms of resistance to covalent BTK inhibitors is development of C481S mutation. Non-covalent BTK inhibitors do not need to bind to C481 residue to inhibitor BTK signaling; hence, they are effective in patients who have developed a resistance to C481S mutation.
“Currently, pirtobrutinib is the only non-covalent BTK inhibitor approved for mantle cell lymphoma. It is not known whether covalent versus non-covalent inhibitors are better for patients with CLL, especially in patients who have not yet received any BTK inhibitors. This is an evolving field of research and randomized clinical trials are planned in this space.”
Oncology Times: What are the key exploratory objectives of the trial, including the evaluation of minimal residual disease negativity, mutation status of BTK and phospholipase C gamma 2 (PLCG2), and biomarker changes in chemokines and B-cell receptor signaling pathway? How will these objectives enhance our understanding of AS-1763 in the context of CLL/SLL and B-cell NHL treatment?
Jain:“AS-1763 is an investigational non-covalent BTK inhibitor currently in phase I clinical trial. The primary objective of this trial is to assess the safety and recommended Phase II dose. Detailed pharmacodynamic analysis will be performed in the clinical trial to assess for biomarkers and B-cell receptor pathway signaling with this agent.”
Dibash Kumar Das is a contributing writer.