Mayo Clinic, Jacksonville, FL
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 , Mingyu Li , Zicong He , Mohammad Ahmad , Hengbang Wang , Asher Alban Akmal Chanan-Khan , Yifan Zhai , Min Yu
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 |
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Disclosures
2024 ASCO Genitourinary Cancers Symposium
First Author: Saby George
2023 ASCO Annual Meeting
First Author: Xuewen Ma
2024 ASCO Annual Meeting
First Author: Masa Lasica
2023 ASCO Annual Meeting
First Author: Kristoffer Staal Rohrberg