Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

person Masa Lasica St. Vincent's Hospital Melbourne, Melbourne, VIC, Australia info_outline Masa Lasica, Sikander Ailawadhi, Chengcheng Fu, Sheeba K. Thomas, Depei Wu, Shuhua Yi, Tanya Siddiqi, Qingsong Yin, John N. Allan, Wenming Chen, Jeffrey V Matous, Ru Feng, Zi Chen, Min Yu, Mingyu Li, Zicong He, Mohammad Ahmad, Hengbang Wang, Asher Alban Akmal Chanan-Khan, Yifan Zhai

Authors person Masa Lasica St. Vincent's Hospital Melbourne, Melbourne, VIC, Australia info_outline Masa Lasica, Sikander Ailawadhi, Chengcheng Fu, Sheeba K. Thomas, Depei Wu, Shuhua Yi, Tanya Siddiqi, Qingsong Yin, John N. Allan, Wenming Chen, Jeffrey V Matous, Ru Feng, Zi Chen, Min Yu, Mingyu Li, Zicong He, Mohammad Ahmad, Hengbang Wang, Asher Alban Akmal Chanan-Khan, Yifan Zhai Organizations St. Vincent's Hospital Melbourne, Melbourne, VIC, Australia, Mayo Clinic Florida, Jacksonville, FL, The First Affiliated Hospital of Soochow University, Suzhou, China, The University of Texas MD Anderson Cancer Center, Houston, TX, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China, City of Hope Comprehensive Cancer Center, Duarte, CA, Henan Cancer Hospital, Zhengzhou, China, Weill Cornell Medicine, New York, NY, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China, Colorado Blood Cancer Institute and Sarah Cannon Research Institute, Denver, CO, Nanfang Hospital, Southern Medical University, Guangzhou, China, Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, China, Ascentage Pharma Group Inc., Rockville, MD, Ascentage Pharma Pty Ltd., Sydney, Australia Abstract Disclosures Research Funding Ascentage Pharma Group Corp. Ltd. (Hong Kong) Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4 mut group (n = 3). No significant difference was observed between pts with/without CXCR4 mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217. Baseline characteristics. Arm A (n = 14) B (n = 24) C (n = 8) Median age, yr (range) 67.5 (48-75) 65.0 (51-92) 65.0 (54-72) Male, n (%) 11 (78.6) 18 (75.0) 6 (75.0) IPSSWM high, n (%) 8 (57.1) 4 (16.7) 2 (25.0) Lines of prior therapies, median (range) 4.0 (1-7) 0 2.5 (1-7) MYD88 + / CXCR4 + 4 9 1 MYD88 + / CXCR4 - 5 13 6 MYD88 - / CXCR4 + 0 0 0 MYD88 - / CXCR4 - 3 1 1

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