Phase 1/2 studies of DZD8586 in CLL/SLL patients after COVALENT and non-COVALENT BTK inhibitors and BTK degraders – extended follow-up report

作者：Keshu Zhou, Tingyu Wang, Wei Yang, Jian‐Qing Mi, Sujun Gao, Huayuan Zhu, Xutao Guo, Kaiyang Ding, Ying Xiang, Huili Cai, Guohui Cui, Yun Zhuang, Hongmei Jing, Liping Su, Rui Huang, Lihua Qiu, Mark B. Geyer, Wuhan Hui, Geoffrey Chong, Meifang Zheng, Yi Wang, Ying Li, Ke Fang, Chan Y. Cheah, Jianyong Li · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-3889 · 被引用次数：2 · 研究领域：Chronic Lymphocytic Leukemia Research、Protein Degradation and Inhibitors、Cancer-related Molecular Pathways

Abstract Background Birelentinib (DZD8586) is a LYN/BTK dual inhibitor designed to block both BTK-dependent and BTK-independent BCR signalling. In TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120) studies, patients who failed front line BTKi and/or BCL2i showed an overall response rate (ORR) of 84.2%. Similar responses were observed in patients with prior treatment of covalent BTKi, non-covalent BTKi as well as BTK degraders, with BTK C481X or “kinase-impaired” mutations (ASCO 2025). Here we report follow-up results of these studies. Methods The data from TAI-SHAN5 and TAI-SHAN8 studies were pooled for the efficacy and safety analysis. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria, as appropriate. All enrolled patients were included in safety analysis, and those patients enrolled by January 2025 were included in efficacy analysis to assess efficacy with long-term follow-up. Results As of July 7, 2025, a total of 65 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). At the recommended phase 3 dose (RP3D), 50 mg QD, 44 patients were enrolled. The median age was 62.5 years, 68% were male, and 64% had ECOG score of 1 or 2. The median number of prior therapies was 2 (range 1-5). Del(17p) and/or TP53 mutation was detected in 37% of the patients. Prior therapies included BTK inhibitor (71%, including 7% treated with non-covalent BTK inhibitor and 5% treated with...