Abstract CT147: Phase I clinical study of Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL)

Abstract Purpose: This clinical study is to evaluate HBW-3220, a novel reversible BTK inhibitor (BTKi) with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (LOXO-305, approved) and MK-1026 (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (the one predominantly enriched in patients resistant to the newer-generation BTKis), and hematopoietic cell kinase (HCK), a key contributor to the development of ibrutinib resistance associated with kinase-defective BTK. Methods: This phase I clinical study was conducted in R/R B-NHL patients who had received two or more prior lines of treatments. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determined whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) were assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5. 0. Response assessment was based on the iwCLL 2018 guidelines, the IWWM-7 consensus, or the Lugano 2014 guidelines, according to the respective disease type. Results: 28 patients have been enrolled so far, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (38%), diarrhea (35%), headache (19%), anemia (42%), infectious pneumonia (23%), decreased neutrophils (42%), decreased platelet count (27%), increased alanine aminotransferase (23%), etc. Drug-related Grade 3 AEs included neutrophil count decreased (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 21 patients underwent at least 1 response assessment (4 chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) ; 4 marginal zone lymphoma (MZL) ; 5 mantle cell lymphoma (MCL) ; 3 diffuse large B-cell lymphoma (DLBCL) ; 5 other B-NHL), and the results are 1 complete response (CR), 6 partial response (PR), and 1 partial response with lymphocytosis (PR-L). The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 2 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 75% (3/4, including 1 PR-L), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR (including CR, PR, and PR-L), 88% (7/8) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK C481S. In the 90 mg and above dose group, the ORR is 47%. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated, showing no DLT occurred at daily doses up to 150 mg, and has good efficacy in patients with CLL/SLL, MZL, and MCL. Citation Format: Ning Lee, Yingfu Li, Yong Mao, Guanfeng Liu, Jiang Li, Qingchun Liu. Phase I clinical study of Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT147.