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

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 BTK degrader), BCL-2 inhibitor (23%), and chemoimmunotherapy (41%). BTK mutations were detected in 55% of patients, including kinase proficient BTK mutation (55%) and kinase impaired BTK mutation (32%). In the efficacy analysis set at RP3D (N=19), 16 out of 19 patients achieved tumor response, with overall response rate (ORR) of 84.2%. Tumor response was observed in patients who received prior treatment with BTK inhibitors (ORR 82.4%, including non-covalent BTK inhibitors [2/2, ORR 100%]), Bcl-2 inhibitor (5/6, ORR 83%), and BTK degrader (1/2, ORR 50%). With median follow-up of 8.3 months, the estimated 12-month PFS rate was 61.9%. As of data cut-off date, the longest responder was on therapy for 12.1 months. DZD8586 was well tolerated across the doses investigated. No new safety signals were identified. At the RP3D, the most common ≥grade 3 drug-related TEAEs were neutropenia (22.7%). No febrile neutropenia was reported. No major bleeding or atrial fibrillation was reported. Nine percent of the patients had drug-related TEAEs leading to dose reduction. Only one patient discontinued treatment due to drug-related TEAE (cough). No drug-related TEAE related death was reported. Conclusion DZD8586 showed encouraging anti-tumor activity with well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader, and Bcl-2 inhibitor treatment. Durable tumor response was observed. The updated data will be presented at the meeting.