Live from ASCO 2024 | Ascentage Pharma Releases Updated Data Showing Promising Efficacy and Safety of Lisaftoclax in Patients with WM
The ASCO Annual Meeting showcases the most cutting-edge research in clinical oncology and state-of-the-art advanced cancer therapies and is the world's most influential and prominent scientific gathering of the clinical oncology community. Presenting clinical development progress at the ASCO Annual Meeting for the seventh consecutive year, Ascentage had four clinical studies of three of the company's proprietary drug candidates selected for presentations, including an oral report, at ASCO 2024.
The latest results from this clinical study validated the favorable safety and efficacy of lisaftoclax monotherapy and in combinations in WM. According to the data, lisaftoclax combined with ibrutinib showed an objective response rate (ORR) of 90.9% in treatment-naïve patients with WM (responses that were unaffected by the CXCR4 mutation), manageable adverse events (AEs), and a low risk of tumor lysis syndrome (TLS). In addition, no potential drug-drug interactions (DDIs) with ibrutinib were observed in the study.
"Lisaftoclax is a novel Bcl-2 selective inhibitor developed to treat malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells," said Dr.
"Lisaftoclax is the first pivotal-stage Bcl-2 inhibitor in
Highlights of these data presented at ASCO 2024 are as follows:
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–
First Author: Masa Lasica, MBBS, FRACP, FRCPA,
Highlights:
Background: Lisaftoclax is a novel, oral, highly selective, potent 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.
*Lisaftoclax is an investigational drug that has not been approved in any country and region.
Appendix: The four clinical studies of
Drug Candidates |
Abstract Title |
Abstract# |
Format |
Olverembatinib |
Updated efficacy results of olverembatinib (HQP1351) in patients with tyrosine kinase inhibitor (TKI)-resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) and paraganglioma. |
#11502 |
Oral Report |
Lisaftoclax ( APG-2575) |
Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia. |
#6541 |
Poster |
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). |
#7078 |
Poster |
|
APG-2449 |
Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors. |
#3124 |
Poster |
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