On June 4, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that it has released updated results from a global, multicenter Phase Ib/II study of the Bcl-2 inhibitor lisaftoclax (APG-2575) alone or in combinations for the treatment of patients with Waldenström macroglobulinemia (WM), in a poster presentation at the 60th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, IL (Press release, Ascentage Pharma, JUN 4, 2024, View Source;ascentage-pharma-releases-updated-data-showing-promising-efficacy-and-safety-of-lisaftoclax-in-patients-with-wm-302164161.html [SID1234644100]). This is the second consecutive year in which this study of lisaftoclax, a key drug candidate in the company’s apoptosis-targeted pipeline, was selected for presentations at the ASCO (Free ASCO Whitepaper) Annual Meeting.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The ASCO (Free ASCO Whitepaper) 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 (Free ASCO Whitepaper) 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 (Free ASCO Whitepaper) 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. Sikander Ailawadhi, the Principal Investigator of the Study from Mayo Clinic. "In this global Phase Ib/II study in patients with relapsed/refractory (R/R) WM, lisaftoclax both as a monotherapy and in combination with ibrutinib or rituximab has shown favorable efficacy that was not negatively affected by the presence of the CXCR4 mutation. In addition, lisaftoclax showed a manageable safety profile with low risk of TLS during daily dose ramp-up. We look forward to seeing more data from this trial."

"Lisaftoclax is the first pivotal-stage Bcl-2 inhibitor in China and the second globally that has demonstrated promising efficacy," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "The updated clinical data of lisaftoclax in WM presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting underscore the drug’s strong therapeutic potential, both as a monotherapy and in combinations, for the treatment of hematologic malignancies. We will continue to advance the clinical development of lisaftoclax with the hope to allow more patients to benefit from the drug as soon as possible."

Highlights of these data presented at ASCO (Free ASCO Whitepaper) 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– 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, 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 Ascentage Pharma’s three drug candidates, including lisaftoclax, presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting.

Drug Candidates

Abstract Title

Abstract#

Format

Olverembatinib
(HQP1351)

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
Presentation

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
Presentation

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.