Novel Agent DZD8586 Shows Promise in Heavily Pretreated CLL
DZD8586 achieved a high response rate in patients with relapsed/refractory CLL/SLL.
Chronic lymphocytic leukemia cells: © Mari-stocker - stock.adobe.com
The investigational treatment DZD8586 elicited encouraging antitumor activity with manageable toxicity in heavily pretreated patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to pooled data from 2 early-phase clinical trials presented at the 2025 ASCO Annual Meeting.1
Tumor responses were observed across all dose levels, with an objective response rate of 84.2% among 19 patients treated at 50 mg daily and 68.8% among 15 patients treated at 75 mg daily. At least some level of tumor shrinkage was observed in 94.1% of 34 evaluated patients.
The recommended phase 3 dose was established as 50 mg daily. Among the 19 evaluable patients receiving this dose, the median treatment duration was longer than 7 months at the data cutoff. Progression-free survival data were not yet mature, with 78.9% of patients still receiving DZD8586 treatment.
“Tumor responses were observed regardless of prior BTK inhibitor, BCL2 inhibitor, or BTK degrader treatment,” said Jianyong Li, MD, PhD, Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China, when reporting the data at ASCO.
There were 30 patients evaluated for safety at the 50 mg recommended phase 3 dose. In this group, the most common treatment-related treatment-emergent adverse events (TEAEs) across all grades were thrombocytopenia (50%), neutropenia (33.3%), pneumonia (13.3%), anemia (13.3%), AST increase (10%), blood creatinine increased (10%), nausea (10%), white blood cell count decreased (6.7%), and ALT increase (3.3%).
The most frequent grade ≥3 treatment-related TRAEs were neutropenia (26.7%), pneumonia (6.7%), thrombocytopenia (3.3%), AST increase (3.3%), and ALT increase (3.3%).
“DZD8586 showed a favorable safety profile at 50 mg daily. There were no major cardiac events, such as QT prolongation or atrial fibrillation, and no drug-related bleeding. Only 1 patient had to discontinue treatment due to TEAEs and there were no treatment-related TEAEs leading to death,” said Li.
Research Background and Patient Characteristics
Explaining the background of the research, Li said, “New therapies are needed for patients with relapsed/refractory CLL/SLL following covalent and/or non-covalent BTK inhibitors…DZD8586 is a rationally designed LYN/BTK dual inhibitor that blocks both BTK-dependent and BTK independent BCR signaling pathways, inhibits resistance mutations against degraders, and shows high selectivity against other TEC family members.”
The findings presented at ASCO were pooled efficacy and safety data for patients with relapsed/refractory CLL/SLL from the phase 1 TAI-SHAN5 trial (NCT05824585) and the phase 2 TAI-SHAN8 trial (NCT06539182, CTR20240120).
Dosing in these trials ranged from 25 mg to 100 mg once daily. The investigators assessed tumor response using either Lugano 2014 or iwCLL 2018 criteria.
Fifty-one patients with relapsed/refractory CLL/SLL had been enrolled as of the cutoff date of April 4, 2025. The median age of the cohort was 63 years (range, 34-84). There were 34 males (66.7%) and 17 females (33.3%). Regarding race, 47 patients (92.2%) were Asian and 4 patients (7.8%) were White. The ECOG performance status was 0 for 20 patients (39.2%) and ≥1 for 31 patients (60.8%).
Available data showed that 14 (40%) of 35 patients had del(17p) and/or TP53 mutations, 15 (35.7%) of 42 patients had BTK C481 mutations, and 8 (19%) of 42 patients had other BTK mutations (eg, L528W, T474I).
The median number of prior treatments was 2, ranging from 1 to 8. The most common previous treatments for CLL/SLL included covalent BTK inhibitors (68.6%; n = 35), non-covalent BTK inhibitors (11.8%; n = 6), BTK degraders (9.8%; n = 5), BCL-2 inhibitors (35.3%; n = 18), and chemoimmunotherapy (56.9%; n = 29).
Looking ahead, ongoing phase 3 research is continuing to explore DZD8586 in patients with relapsed/refractory CLL.
