Lisaftoclax Plus Azacitidine Shows Clinical Activity and Manageable Safety in Higher-Risk MDS

The combination of the novel BCL-2 inhibitor lisaftoclax (APG-2575) and azacitidine (Vidaza) demonstrated clinical activity and had a manageable safety profile in patients with treatment-naive or relapsed/refractory higher-risk myelodysplastic syndromes (MDS), according to findings from a phase 1b/2 study (NCT04501120) presented at the 2024 ASH Annual Meeting.

Data showed that treatment-naive patients with higher-risk MDS treated with lisaftoclax at 600 mg per day plus azacitidine (n = 23) achieved an overall response rate (ORR) of 73.9%, including a complete remission (CR) rate of 30.4% per 2006 International Working Group (IWG) criteria. The composite CR rate based on 2023 IWG criteria was 69.6%, including 52.2% of patients achieving CR and 17.4% experiencing CR with limited count recovery. The median time to CR in this group was 2.8 months (range, 1.1-8.7), and the median progression-free survival (PFS) was not reached (95% CI, 7.1-NR).

Among all patients with treatment-naive higher-risk MDS (n = 40) treated with lisaftoclax at 400 mg per day (n = 16), 600 mg per day (n = 23), or 800 mg per day (n = 1) plus azacitidine experienced an ORR of 77.5% and a CR rate of 25.0%. In all patients with relapsed/refractory higher-risk MDS (n = 8) treated with lisaftoclax at 600 mg (n = 5) or 800 mg (n = 3) plus azacitidine, the ORR and CR rate were 75.0% and 12.5%, respectively.

"In patients with higher-risk treatment-naive or relapsed/refractory MDS, lisaftoclax combined with azacitidine showed encouraging activity and was well tolerated,” lead study author Huafeng Wang, MD, of Zhejiang University in Hangzhou, China, and colleagues wrote in a poster presentation of the data.

The most common grade 3 or higher hematologic treatment-related adverse effects (TRAEs) included leukopenia (71.4%), neutropenia (65.3%), thrombocytopenia (61.2%), anemia (20.4%), and febrile neutropenia (12.2%). Infections that were grade 3 or higher were observed in 46.9% of patients, and 26.5% were considered treatment related. Serious treatment-emergent and -related AEs were reported in 34.7% and 28.6% of patients, respectively.

Lisaftoclax dose reductions due to TRAEs occurred in 6.1% of patients (n = 3), including neutropenia (n = 2)and thrombocytopenia (n = 1). Treatment delays between cycles due to AEs were reported in 22.4% of patients with a median delay of 12 days (range, 1-63). No instances of tumor lysis syndrome (TLS) or 60-day mortality were observed.

Study Design

In this trial, investigators enrolled patients with higher-risk MDS, defined as an International Prognostic Scoring System-Revised (IPSS-R) score greater than 3.5 and bone marrow blast levels greater than 5%. Patients were allowed to have treatment-naive or relapsed/refractory disease.

All enrolled patients received lisaftoclax at assigned doses of 400 mg, 600 mg, or 800 mg, administered orally once daily from days 1 to 14 of each 28-day treatment cycle. Lisaftoclax was combined with azacitidine at a standard dose of 75 mg/m² per day on days 1 to 7 of each cycle. To mitigate the risk of TLS, a daily lisaftoclax ramp-up schedule was implemented before the first treatment cycle.

Patients continued treatment until disease progression, unacceptable toxicity, or withdrawal of consent.

Efficacy assessments were performed at the end of cycle 1 and subsequently at the end of every even-numbered cycle. Responses were evaluated according to the 2006 IWG criteria, with additional assessments using the updated 2023 IWG criteria for the 600-mg, treatment-naive cohort.

The primary end point of the trial was safety, specifically regarding the incidence of TLS and hematologic toxicities. Secondary end points included ORR, DOR, PFS, and overall survival.

Patient Demographics

As of July 1, 2024, a total of 49 patients were enrolled in the phase 1b/2 trial. Of these, 8 patients (16.3%) had relapsed/refractory MDS, and 41 patients (83.7%) were treatment-naive.

The median age of all enrolled patients was 66 years (range, 22-83), and 55.1% male. IPSS-R scores included intermediate-risk (24.5%), high-risk (49.0%), and very high–risk (26.5%).

Among the patients with available genetic mutational profiling (n = 39), the most common mutations identified included TET2 (28.2%), TP53 (23.1%), ASXL1 (25.6%), and RUNX1 (25.6%).

Baseline grade 3 or higher cytopenias included anemia (70.8%), neutropenia (54.2%), and thrombocytopenia (45.8%).

The median duration of treatment was 4.5 months (range, 0.5-12.1) for treatment-naive patients and 3.2 months (range, 1.2-9.4) for those with relapsed/refractory disease.

“The clinical data support further clinical development of this combination in patients with higher-risk MDS,” study authors noted.

The randomized, double-blind, phase 3 registrational GLORA-4 trial (NCT06641414) will further assess the lisaftoclax combined with azacitidine vs placebo plus azacitidine in patients with newly diagnosed, higher-risk MDS.

Reference

Wang H, Wei X, Yang L, et al. A phase 1b/2 study of lisaftoclax (APG-2575), a BCL-2 inhibitor, in combination with azacitidine for the treatment of patients with myelodysplastic syndrome (MDS). Blood. 2024;144(suppl 1):3202 doi:10.1182/blood-2024-205371