ASCO2024|Updated Data of Lisaftoclax Plus Azacitidine in AML

Prof. Jie Jin

A Principal Investigator of the study from the First Affiliated Hospital, Zhejiang University School of Medicine

“As a proprietary novel Bcl-2 inhibitor, lisaftoclax has shown treatment responses comparable to the approved Bcl-2 inhibitor and a better safety profile. The improved safety offered by lisaftoclax means lower treatment-related mortality, fewer dose adjustments, and earlier start of sequential chemotherapies that should contribute to patients’ long-term survival.”

Dr. Huafeng Wang

The presenter of the poster from the First Affiliated Hospital, Zhejiang University School of Medicine

“The introduction of Bcl-2 inhibitors represents a major breakthrough for the treatment of AML. However, the hematologic safety issues associated with the approved Bcl-2 inhibitor have limited the clinical adoption and the long-term efficacy. As a novel drug, lisaftoclax was frequently presented and attracted broad interest. When combined with chemotherapies, lisaftoclax showed a rate of hematologic adverse events that was lower than that of the approved Bcl-2 inhibitor. More importantly, its hematologic adverse events were relatively mild and easy to manage. Its hematologic toxicity-related serious adverse events such as neutropenic fever and 30-/60-day mortalities were very low. This suggests that lisaftoclax-associated hematologic toxicities are transient, less serious, easier to manage, and therefore would have less negative impact on sequential chemotherapies. Overall, lisaftoclax has already shown a highly favorable clinical potential.”

Dr. Yifan Zhai

Chief Medical Officer of Ascentage Pharma

“These efficacy and safety data of lisaftoclax combined with AZA in patients with AML are very encouraging because they reaffirmed the drug’s global best-in-class potential as a hopeful new treatment option for patients with AML, a hematologic malignancy commonly associated with a poor prognosis. A global registrational Phase III study of lisaftoclax in AML is already underway. Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will accelerate the clinical development of lisaftoclax and bring this novel therapeutic to the broad population of patients with AML as soon as possible.”

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.

Abstract#: 6541

Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant

Date and Time: June 3, 2024, Monday, 9:00 AM – 12:00 PM (Central Time)

First Author: Huafeng Wang, MD, PhD, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Highlights:

Background and introduction : Early studies showed that lisaftoclax in combination with various agents can synergistically induce apoptosis in AML. This poster presents follow-up safety and efficacy data from a Phase Ib/II study of lisaftoclax combined with AZA in adults with AML.

Patient enrollment and methods :

• This study enrolled elderly (≥75 years)/unfit TN patients with AML who were intolerant of standard induction chemotherapies and patients (≥18 years) with R/R AML. Lisaftoclax (400/600/800 mg) was administered orally once daily in 28-day cycles. In the first treatment cycle, a daily ramp up schedule was used to prevent TLS. AZA was administered once daily on D1-D7 at 75 mg/m ² .

• As of January 25, 2024, 76 patients with AML were enrolled, including 37 patients with R/R AML and 39 elderly/unfit patients with TN AML who were intolerant of standard induction chemotherapies. The median (range) age was 66 (20-81) years.

Efficacy results :

• In patients with R/R AML treated with lisaftoclax combined with AZA, the overall response rate ([ORR]=CR + CRi + morphologic leukemia-free state [MLFS] + PR) was 72.7%, and the composite complete remission rate (CRc = CR + CRi) was 45.5%. In the 600 mg cohort (n=30), the median duration of treatment was 3.8 months, the ORR was 76.7%, the CRc was 50.0%, the median time to CRc was 2.5 months, the median PFS was 10.2 months, and the median overall survival (OS) was 14.7 months.

• Among patients with TN AML treated with lisaftoclax combined with AZA, the ORR was 64.1%, and the CRc was 51.3%. In the 600 mg cohort (n=29), the median duration of treatment was 3.3 months, and the median time to CRc was 1.9 months. The median PFS and median OS were not reached.

• 600 mg lisaftoclax combined with AZA was established as the recommended Phase II dose (RP2D).

Safety results : All patients treated with lisaftoclax combined with AZA reported treatment-emergent adverse events (TEAEs), with 89.5% experiencing grade 3/4 TEAEs and 43.4% experiencing serious adverse events (SAEs). Common Grade ≥ 3 TEAEs reported in ≥ 10% of patients included neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported. The 30-day mortality rate was 1.3%.

Conclusions : These data support a promising role for the new Bcl-2 inhibitor lisaftoclax combined with AZA for the treatment of elderly/unfit TN patients with AML intolerant of standard induction chemotherapies and patients with R/R AML, especially given a potentially favorable safety profile in terms of TLS, the incidence of neutropenic fever, and low early mortality. A Phase III randomized, double-blind study is being conducted to determine whether lisaftoclax combined with AZA improves the survival of elderly/unfit TN patients with AML intolerant of standard induction chemotherapies.

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