Phase 1/2 Studies of DZD8586, a Non-Covalent BBB Penetrant LYN/BTK Dual Inhibitor, in BTK Inhibitor Resistant Chronic Lymphocytic Leukemia (CLL) and Other B-Cell Non-Hodgkin Lymphoma (B-NHL)
Year: 2024
Type: conference-abstract
Abstract: Introduction Covalent BTK inhibitors (BTKi) are highly effective, but treatment resistance typically occurs. Two types of resistance mutations have been identified after BTK inhibitor treatment. The C481X mutation disrupts covalent BTK inhibitors' binding to BTK enzyme and leads to treatment failure. Paradoxically, the dominant clinical resistance mutations to non-covalent BTK inhibitor such as pirtobrutinib cause loss of or much diminished BTK enzyme activity, suggesting a BTK-independent resistance mechanism. Previously, we have shown the critical role of LYN-AKT pathway downstream of B cell receptor as the main BTK-independent resistance mechanism. DZD8586 was designed as a LYN/BTK dual inhibitor with full blood-brain barrier (BBB) penetration and high selectivity against other TEC family kinases (TEC, ITK, TXK, BMX). Here we report results from ongoing Phase 1/2 clinical studies showing DZD8586's clinical efficacy and safety in patients whose diseases have progressed after BTKi treatment, with and without BTK C481X mutations. Methods The data from three clinical studies, TAI-SHAN1 (NCT05844956; CTR20220558), TAI-SHAN8 (CTR20240120) and TAI-SHAN9 (CTR20240121), were pooled for the safety and efficacy analysis. TAI-SHAN1 is a phase 1 dose escalation study for patients with r/r CLL and NHL, TAI-SHAN8 is a phase 2 study in r/r CLL and TAI-SHAN9 is a phase 2 study in r/r DLBCL. Patients with B-cell lymphoma (B-NHL) including CNS lymphoma and CLL with disease progression or intolerance to prior therapies were enrolled. Modulation of PD biomarkers was evaluated at doses tested. Tumor responses were assessed by investigators per Lugano 2014, IPCG 2005, or iwCLL 2018 criteria, as appropriate. Results As of July 1, 2024, a total of 38 patients with r/r B-NHL have been enrolled and received DZD8586 at doses ranging from 10 mg to 100 mg once daily (QD) (10 mg，n=1；25 mg，n=11；50 mg，n=19；100 mg，n=7). The median age was 59 years, 60.5% were male. The percentage of patient with ECOG of 0/≥1 were 42.1%/57.9%. Histological subtypes included DLBCL, CLL/SLL, FL, MZL, secondary CNS lymphoma and MCL. The median number of prior therapies was 2 (range 1 - 8). Common anti-cancer therapies included chemoimmunotherapy therapy (n=33, 86.8%), BTK inhibitor (n=15, 39.5%), and Bcl-2 inhibitor (n=4, 10.5%). DZD8586 was well tolerated across the doses investigated. The most common ≥ grade 3 TEAEs were thrombocytopenia (13.2%, all at 100 mg) and neutropenia (13.2%). Other ≥ grade 3 TEAEs reported in ≥ 2 patients, including pneumonia (7.9%) and hypokalaemia (5.3%). All these TEAEs were reversible after dose interruption and/or with supportive care. No bleeding, atrial fibrillation, or arthralgias were reported. PK was generally dose-proportional across the dose ranges of 10 mg to 100 mg. Dose dependent pBTK modulation was detected in whole blood cells. In 2 patients with CNSL, the unbound CSF to plasma concentration ratio at steady state were 1.21 and 0.98, suggesting high BBB penetration of DZD8586. At 25 mg, the mean pBTK inhibition reached ~90% at steady state, and at ≥ 50 mg, sustained >90% pBTK inhibition was observed at all time points tested. In addition, two patients with C481S mutation achieved plasma ctDNA clearance with DZD8586 treatment at 50 mg. A total of 24 patients had at least one post-treatment tumor assessment, and there was a dose dependent increase of ORR (25 mg, 25%; 50 mg, 44.4%; 100 mg, 83.3%). Three patients achieved complete response. Responses were observed across histologic subtypes. At doses ≥ 50 mg QD, 2 out of 5 patients with prior BTK inhibitor treatment achieved tumor response, including one complete response. One out of 2 patients with prior Bcl-2 inhibitor treatment achieved complete response. As of the data cut-off date, the longest responder was on therapy for 13.2 months (treatment ongoing). Based on PK, PD and efficacy data, dose levels ≥50 mg QD will be further explored to define the recommended phase 2 dose. Conclusion DZD8586 has encouraging anti-tumor activity and an acceptable safety profile in heavily pre-treated B-NHL and CLL patients, including among patients with prior covalent BTKi exposure. PK/PD results confirmed dose-dependent pathway inhibition by DZD8586, with good BBB penetration. Enrolment continues, and updated data will be presented at the meeting.
Source: Blood
Authors: Yuqin Song, Keshu Zhou, Hongmei Jing, Geoffrey Chong, Jianqiu Wu, Wei Liu, Zengjun Li, Ming Jiang, Mei Lan, Kaiyang Ding, Guohui CUI, Tingyu Wang, Xutao Guo, Sujun Gao, Constantine S. Tam, Haiyan Yang, Fang Zhu, Wei Yang, Jian-Qing Mi, Liping Su, Ke Fang, Ziyi Liu, Lindsey Roeker, Chan Y. Cheah, Jianyong Li, Lu-Gui Qiu
Institutions: Peking University Cancer Hospital, Zhengzhou University, Henan Cancer Hospital, Peking University, Peking University Third Hospital, Austin Hospital, Olivia Newton-John Cancer Wellness & Research Centre, Jiangsu Cancer Hospital, Nanjing Medical University, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital, Shandong First Medical University, Sichuan University, West China Hospital of Sichuan University, The People's Hospital of Guangxi Zhuang Autonomous Region, Huazhong University of Science and Technology, State Key Laboratory of Experimental Hematology, Nanfang Hospital, Southern Medical University, First Hospital of Jilin University, Monash University, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Wuhan Union Hospital, Sheng Jing Hospital, China Medical University, Shanghai Jiao Tong University, Ruijin Hospital, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Shanxi Provincial Cancer Hospital, Dizal (Jiangsu) Pharmaceutical Co., Ltd. (China), Memorial Sloan Kettering Cancer Center, Sir Charles Gairdner Hospital, Jiangsu Province Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405038930