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3248 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)

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Adult, Lymphomas, Non-Hodgkin lymphoma, Drug development, Clinical Research, B Cell lymphoma, Diseases, Treatment Considerations, Lymphoid Malignancies, Study Population, Human
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Yuqin Song, MD1, Keshu Zhou, MD2*, Hongmei Jing, MD3, Geoffrey Chong4, Jianqiu Wu, PhD5*, Wei Liu, MD6*, Zengjun Li7*, Ming Jiang, PhD8*, Mei Lan, MD9*, Kaiyang Ding10*, Guohui CUI11*, Tingyu Wang12*, Xutao Guo, MD13*, Sujun Gao14*, Constantine S. Tam, MBBS, MD15, Haiyan Yang, PhD16, Fang Zhu17*, Wei Yang18*, Jian-Qing Mi19, Liping Su20, Ke Fang21*, Ziyi Liu21*, Lindsey Roeker, MD22, Chan Y. Cheah, MBBS DMSc23, Jianyong Li, MD24 and Lu-Gui Qiu, MD6

1Department of Lymphoma, Peking University Cancer Hospital, BEIJING, China
2Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
3Peking University Third Hospital, Beijing, China
4Olivia Newton-John Cancer Wellness & Research Centre, Austin Hospital, Heidelberg, VIC, Australia
5Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Nanjing Medical University Affiliated Cancer Hospital, Nanjing, AL, China
6State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology& Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
7Cancer Hospital of Shandong First Medical University, Jinan, China
8West China Hospital,Sichuan University, Chengdu, China
9The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, CHN
10Department of Hematological, Anhui Province Cancer Hospital, Hefei, China
11Union Hospital, Tongji Medical College,Huazhong University of Science and Technology, WUHAN, CHN
12State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sci, Tian Jin, China
13Department of Hematology, Nanfang Hospital of Southern Medical University, GuangZhou, China
14Department of Hematology, The First Hospital of Jilin University, Changchun, China
15Monash University, Melbourne, VIC, Australia
16Department of Lymphoma, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
17Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Sc, Wuhan, CHN
18Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
19Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
20Shanxi Province Cancer Hospital, Taiyuan, China
21Dizal Pharmaceutical, Shanghai, China
22Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
23Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
24First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China

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.

Disclosures: Chong: Amgen, AstraZeneca, Bayer, Dizal Pharma, HUTCHMED, Incyte, Innate Pharma, Merck, Pfizer, Pharmacyclics, Roche: Research Funding; Bristol Myers Squibb, Regeneron Pharmaceuticals, Inc.: Consultancy, Research Funding; Takeda: Consultancy. Tam: AbbVie, BeiGene, Janssen, LOXO: Honoraria; AbbVie, BeiGene, Janssen: Research Funding. Fang: Dizal Pharmaceutical: Current Employment. Liu: Dizal Pharmaceutical: Current Employment. Roeker: AbbVie: Consultancy, Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; Qilu Puget Sound Biotherapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Pfizer: Consultancy, Research Funding; PeerView: Honoraria, Speakers Bureau; Medscape: Honoraria, Speakers Bureau; Loxo Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Genentech: Research Funding; Dren Bio: Research Funding; Adaptive Biotechnologies: Research Funding; Dava Oncology: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Aptose Biosciences: Research Funding; Curio: Honoraria, Speakers Bureau; Ascentage: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy. Cheah: Sobi: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding, Speakers Bureau; Dizal: Consultancy, Honoraria; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH