Impact of Docirbrutinib (AS-1763) Treatment in CLL: Preclinical Data and Early Clinical Biomarkers

• Published in: Blood 2024-11, Vol.144, p.1850-1850
• Main Authors: Timofeeva, Natalia, Herrera, Breana, Tantawy, Shady I., Fujiwara, Hitomi, Loza, Lizbeth, Hatakeyama, Mariko, Asami, Tokiko, Ohmoto, Hiroshi, Miyamoto, Kyoko, Nishioka, Yu, Arimura, Akinori, Sawa, Masaaki, Jain, Nitin, Gandhi, Varsha
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-210788

Background: Non-covalent BTK inhibitors (ncBTKi), such as pirtobrutinib, have emerged as critical therapeutic options for patients (pts) with chronic lymphocytic leukemia (CLL). These ncBTKi are highly relevant as they provide an alternative mechanism of action, bypassing the common resistance associated with covalent BTK inhibitors (cBTKi) that target the C481 residue. However, non-C481 mutations have been identified as contributors to pirtobrutinib resistance, further emphasizing the need for effective ncBTKi therapies. At ASH 2023 our group presented data introducing a potent, highly selective, orally available ncBTKi, AS-1763 (docirbrutinib). Building on these foundational results, our current work expands the study by preclinical and clinical investigations. Study Design and Methods: We used cell free assay systems to evaluate selectivity and potency of docirbrutinib against 15 BTK-mutants including predicted potential double mutants. We further validated potency of docirbrutinib in cells by measuring inhibition of BTK autophosphorylation in BTK-mutant-transfected HEK293 cell lines. Biological and biochemical effects were tested in treatment-naïve (TN with BTK-wild type) and relapsed/refractory (R/R with BTK and/or Bcl-2 mutant) CLL cells during in vitro investigations with 0.01, 0.1, and 1 µM docirbrutinib alone or with Bcl-2i (venetoclax) or Mcl-1i (AZD5991). Finally, we investigated biomarkers in longitudinal samples obtained from pts during dose-escalation docirbrutinib clinical trial in R/R CLL (NCT05602363 Clinical Trials.gov). Results: We have generated a total of 15 recombinant BTK mutant proteins (C481, T474, L528, T316 variants and double mutants). Docirbrutinib showed potent inhibitory activities for those BTK mutants while inhibitory potencies of ibrutinib or pirtobrutinib were diminished against some BTK mutants such as C481 or T474 and L528, respectively. Docirbrutinib inhibited BTK autophosphorylation (pY223) in HEK293 cells transfected with those BTK mutants. In proliferation assays, docirbrutinib inhibited cell growth of c/ncBTKi-resistant OCI-Ly10 cells harboring mutant BTKs (C481S, T474I or L528V). In TN CLL lymphocytes from 11 CLL pts, 72-hr incubation with docirbrutinib induced modest yet significant apoptosis which was comparable to ibrutinib or pirtobrutinib. In parallel, B-cell activation, as measured by surface expression of CD86 in cells (n=14 CLL pts), was inhibited with 10 and 100 nM docirbrutinib (p=