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).
Abstract#:
7078
Session Title:
Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
Date and Time:
June 3, 2024, Monday, 9:00 AM– 12:00 PM (Central Time)
First Author:
Masa Lasica, MBBS, FRACP, FRCPA, St Vincent’s Hospital, Melbourne, Victoria, Australia.
Highlights:
Background
: Lisaftoclax is a novel, oral, highly selective, pot
ent Bcl-2 inhibitor. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax combined with ibrutinib has a strong synergistic effect.
Introduction
: This was an open-label, multicenter, global Phase Ib/II study designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of lisaftoclax monotherapy or in combinations with agents such as ibrutinib/rituximab in patients with WM.
Patient enrollment and methods
:
-
In this study, patients with WM were enrolled in 3 arms, including Arm A: lisaftoclax monotherapy in patients resistant to or intolerant of prior treatment with Bruton's tyrosine kinase inhibitors (BTKis); Arm B: lisaftoclax combined with ibrutinib in treatment-naïve patients with WM; and Arm C: lisaftoclax combined with rituximab in BTKi-naïve patients with relapsed/refractory WM.
-
Lisaftoclax was orally administered once daily in 28-day cycles. Lisaftoclax was gradually escalated from the starting dose of 400 mg to 1,200 mg. As of January 25, 2024, a total of 46 patients were enrolled in the study (Arm A [n=14] at doses of up to 1,000 mg; Arm B [n=24] at doses of up to 1,200 mg; Arm C [n=8] at doses of up to 800 mg).
Efficacy results
:
-
The median (range) durations of treatment were 11 (1-28), 23.5 (1-34), and 11.5 (5-33) months for Arms A, B, and C, respectively.
-
The ORRs (PR, very good partial response [VGPR], CR) were 41.7%, 90.9%, and 37.5% for Arms A, B, and C, respectively.
-
In Arm A, patients with wild-type
CXCR4
(n =7) had better overall responses to lisaftoclax than the
CXCR4
mutation group (n = 3).
-
In Arms B and C, no significant differences between patients with/without
CXCR4
mutation were observed.
Safety results
:
-
In Arm B, 1 dose-limiting toxicity (DLT, grade 3 clinical TLS), in the setting of anticipated renal impairment, occurred at 1,200 mg; and 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg. Abnormal electrolytes was resolved without recurrence after 1 day of drug interruption.
-
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% in the setting of neutropenia).
-
Ventricular arrhythmia was not observed.
-
One patient required dose reduction because of neutropenia.
-
The maximum-tolerated dose (MTD) was not reached.
-
Lisaftoclax combined with ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential DDIs.
Conclusions
: Lisaftoclax alone or combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in patients with treatment-naïve or BTKi-treatment-failed WM.
