AFFILIATIONS
1 Department of Hematology, Institute of Hematology, and Center for High Altitude Medicine, West China Hospital, Sichuan University, Cheng Du, China, National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University., Cheng Du, China
2 Peking University Third Hospital, Beijing, China
3 The First Bethune Hospital of Jilin University, Jilin, China
4 Department of Hematology, Institute of Hematology, and Center for High Altitude Medicine, West China Hospital, Sichuan University, Cheng Du, China, National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University., Cheng Du, China
5 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China
6 Changzhou First People's Hospital, Third Affiliated to Soochow University, Changzhou, China
7 Nanfang Hospital of Southern Medical University, Guangzhou, China
8 Department of Haematology, Institute of Hematology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Huhan, China
9 Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
10 Department of Hematology, Zhujiang Hospital, Southern Medical University, Zhujiang, China
11 Department of Hematology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Anhui, China
12 First Affiliated Hospital of Nanchang University, Nanchang, China
13 Yichang Central People's Hospital, Yichang, China
14 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan, China
15 Hunan Cancer Hospital, Changsha, China
16 Dizal Pharmaceutical Co., Ltd., shanghai, China
17 Dizal Pharmaceutical Co., Ltd., shanghai, China
18 Department of Hematology, Institute of Hematology, and Center for High Altitude Medicine, West China Hospital, Sichuan University, Cheng Du, China, National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University., Cheng Du, China
19 Department of Hematology, Institute of Hematology, and Center for High Altitude Medicine, West China Hospital, Sichuan University, Cheng Du, China, National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University., Cheng Du, China
20 Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, China
21 Department of Hematology, Institute of Hematology, and Center for High Altitude Medicine, West China Hospital, Sichuan University, Cheng Du, China, National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University., Cheng Du, China
ABSTRACT
Introduction
Birelentinib (DZD8586) is a novel dual LYN-BTK inhibitor, designed to completely block BCR signalling pathway. Preclinically, birelentinib demonstrated potent antitumor activity in both BTK-dependent and BTK-independent tumor models. Venetoclax treatment resulted in feedback upregulation of MCL1, a member of the BCL2 anti-apoptotic gene family, which has been proposed as a primary mechanism of acquired resistance to venetoclax. Unlike other BTK only inhibitors, birelentinib, when combined with venetoclax, significantly prevented MCL1 upregulation, due to its dual inhibition of LYN and BTK. Consistent with this finding, birelentinib-venetoclax achieved deeper and more durable regression than venetoclax with ibrutinib or pirtobrutinib or other BTK inhibitors. Based on these results, we evaluated the efficacy and safety of birelentinib in combination with venetoclax in treatment naïve (TN) CLL/SLL patients.
Methods
TAI-SHAN10 (NCT07154264) is a phase II study. Part A of the study includes dose escalation and determination of dose-limiting toxicities (DLTs). Part B is dose expansion to further evaluate safety and efficacy.
Patients received birelentinib as monotherapy for a 3-cycle lead-in period, 28 days per cycle, followed by combination therapy of birelentinib plus venetoclax (ramp-up to 400 mg QD) from cycle 4 to cycle 28 (depending on whether early stopping criteria were met). Patients who met the early stopping criteria would discontinue birelentinib and venetoclax treatment. After cycle 28, those who did not meet the early stopping criteria would continue with birelentinib monotherapy until disease progression or unacceptable toxicity. Antitumor efficacy was assessed by investigators per iwCLL 2018 or Lugano 2014.
Results
As of June 17, 2026, a total of 26 patients with TN CLL/SLL had been enrolled and treated with ≥1 dose of investigational therapy (birelentinib 50 mg QD, with or without venetoclax). The median age was 52 years (range, 29 - 77), and 65.4% were male. At baseline, high-risk genetic features included unmutated IGHV (30.8%), del(17p) and/or TP53 mutation (15.4%), and complex karyotype (19.2%).
All 26 patients were included in the safety analysis. By the data cut-off date, 25 patients (96.2%) remained on the study, and one discontinued due to patient withdrawal. No DLTs were observed during the DLT observation period. A total of 8 patients (30.8%) experienced at least one ≥ grade 3 drug-related TEAEs. Common ≥ grade 3 drug-related TEAEs were neutropenia, anemia, decreased white blood cell count and hypertension. A total of 4 patients (15.4%) experienced at least one treatment-emergent SAE, which included pneumonia (1 patient) and pyrexia (3 patients). No clinical or laboratory TLS occurred, and no drug-related TEAEs led to dose reductions, discontinuations or deaths.
A total of 21 patients completed at least one post-treatment tumor assessment. Among them, 14 patients had at least one efficacy assessment after initiating combination therapy. With median follow-up of 4.6 months, no disease progression and death events had been reported. All patients achieved an objective response at the first tumor assessment following 2 cycles of combination therapy. The overall response rate (ORR) was 100%, including a CR/CRi rate of 14.3%. Clinical activity was also observed in patients with high-risk genetic features. Disease remission was rapidly achieved in all patients, irrespective of high-risk features. Among patients with unmutated IGHV, one patient achieved CR, corresponding to a CR rate of 20% (1 out of 5). Birelentinib 50 mg QD plus venetoclax (target dose 400 mg QD) was defined as the recommended phase 3 combination doses.
Conclusion:
Birelentinib plus venetoclax demonstrated promising antitumor activity with well-tolerated safety profile in patients with TN CLL/SLL, regardless of del(17p) and/or TP53 mutation or IGHV mutational status. The updated safety and efficacy data, including MRD negativity rate, will be presented at the meeting.