Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

Sikander Ailawadhi Mayo Clinic, Jacksonville, FL info_outline Sikander Ailawadhi, Masa Lasica, 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 Sikander Ailawadhi Mayo Clinic, Jacksonville, FL info_outline Sikander Ailawadhi, Masa Lasica, 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 Mayo Clinic, Jacksonville, FL, St Vincent's Hospital, Melbourne, Melbourne, VIC, Australia, 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, Denver, CO, Nanfang Hospital, Southern Medical University, Guangzhou, China, Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, China, Ascentage Pharma (Suzhou) Co., Ltd, Suzhou, China, Ascentage Pharma Group Inc., Rockville, MD, Jiangsu Ascentage Pharma Pty Ltd., Sydney, NSW, Australia, Mayo Clinic Florida, Jacksonville, FL Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Ascentage Pharma Group Corp Ltd Background: B-cell lymphoma 2 inhibitors (BCL-2i) are well tolerated and effective in treating B-cell lymphoproliferative disorders such as CLL. Investigational agent lisaftoclax is a novel, oral, highly selective and potent BCL-2i. Preclinical data show a strong synergistic effect of lisaftoclax plus ibrutinib in an ibrutinib-insensitive PDXWM1 model. Methods: This global, open-label, multicenter study evaluates the safety and efficacy of lisaftoclax alone and combined with ibrutinib or rituximab in pts with WM. Pts were enrolled in 3 arms: Arm A (lisaftoclax), BTKi-resistant/intolerant pts; Arm B (lisaftoclax plus ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax plus 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 TLS risk. Primary objectives were pharmacokinetics (PK), safety, and efficacy assessments; responses were assessed per IWWM criteria. Results: As of January 25, 2023, 46 pts were enrolled (Arm A [n = 14]; up to 1,000 mg; Arm B [n = 24]; up to 1,200 mg; Arm C [n = 8]; up to 800 mg). Baseline characteristics are shown in the table. Median (range) treatment duration was 6 (1-18; Arm A), 14 (1-27; B), and 8 (2-26; C) months. Overall response rates (ORRs) were: Arm A, 25% (median time to response [MTTR], 4.3 months); Arm B, 90.9% (MTTR, 1.9); Arm C, 37.5% (MTTR, 4.4). No significant difference was observed between pts with and without CXCR4-mut. At 1,200 mg, 1 DLT (grade 3 clinical TLS), due to pre-existing renal impairment, was reported. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic therapies; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. Only 1 pt required dose reduction (due to neutropenia). MTD has not been reached. A total of 14 pts discontinued study treatment because of disease progression (n = 5) and AE (n = 1). Lisaftoclax plus ibrutinib showed a PK exposure comparable to ibrutinib alone, indicating no potential DDI. Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. Internal study identifier: APG2575WU101. *SA and ML are co-first authors. Clinical trial information: NCT04260217. Arm A (n = 14) B (n = 24) C (n = 8) Median age, y (range) 67.5 (48-75) 65.0 (51-92) 65.0 (54-72) Male, no. (%) 11 (78.6) 18 (75.0) 6 (75.0) IPSSWM high, no. (%) 8 (57.1) 4 (16.7) 2 (25.0) Lines of prior therapies, median (range) 4.0 (1-7) 0 1.5 (1-7) MYD88+/CXCR4 + 3 7 1 MYD88+/CXCR4- 5 14 6 MYD88-/CXCR4 + 0 1 0 MYD88-/CXCR4- 5 1 1

Clinical