Phase 1/2 studies of DZD8586 in CLL/SLL patients after covalent or non-covalent BTK inhibitors and BTK degraders.

Abstract

7010 Background: New therapies are needed for patients with relapsed or refractory (r/r) CLL/SLL following covalent and/or non-covalent BTK inhibitors. While early clinical data showed encouraging anti-tumor activities from BTK degraders in these patients, resistance mutations to both BTK inhibitors and degraders have already been reported. In addition, concerns with emerging clinical safety signals from these degraders may limit their longer-term clinical use. DZD8586 is a rationally designed LYN/BTK dual inhibitor with high selectivity against other TEC family members. Here we report results from ongoing phase 1/2 clinical studies of DZD8586 in r/r CLL/SLL patients with prior treatment of covalent and/or non-covalent BTK inhibitors as well as BTK degraders. Methods: The data from two clinical studies, TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120), were pooled for the safety and efficacy analysis in patients with CLL/SLL. Modulation of PD biomarkers was evaluated at doses tested. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria as appropriate. Results: As of January 3, 2025, a total of 40 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). The median age was 64.5 years, 62.5% were male, and 60% had ECOG score of 1 or 2. A total of 30 patients were evaluable for efficacy analysis. The median number of prior therapies was 2 (range 1-8). Most common prior CLL/SLL therapies included BTK inhibitor (76.7%), and Bcl-2 inhibitor (43.3%). Patients previously treated by non-covalent BTK inhibitor (13.3%) and BTK degrader (13.3%) were also reported. Across all dose levels, 15 out of 30 patients achieved tumor response, with objective response rate (ORR) of 50%. At the recommended phase 2 dose (RP2D) of 50 mg QD, 9 out of 14 patients achieved tumor response, with ORR of 64.3%. Efficacy was observed in patients with prior BTK inhibitor treatment (ORR 52.2%), and Bcl-2 inhibitor treatment (ORR 46.2%). Seventy five percent patients who received prior BTK degrader treatment achieved partial response. As of the data cut-off date, the longest responder was on therapy for 12.1 months. Deepening response was observed with longer treatment time. DZD8586 was well tolerated across the doses investigated. At the RP2D, the most common ≥grade 3 TEAEs were neutropenia (15%) and pneumonia (10%). No major bleeding or atrial fibrillation was reported. No grade 4/5 AEs reported. Conclusions: DZD8586 showed encouraging anti-tumor activity with a 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. PK/PD results confirmed dose/exposure-dependent pathway inhibition by DZD8586. The updated data will be presented at the meeting. Clinical trial information: NCT06539182 , NCT05824585 .