GLORA-4 Set to Evaluate Lisaftoclax Plus Azacitidine in Higher-Risk MDS in First-of-Its-Kind Study

After lisaftoclax (APG-2575) showed intriguing early-phase efficacy in combination with azacitidine (Vidaza) for the treatment of patients with higher-risk myelodysplastic syndromes (MDS), both in the relapsed/refractory and frontline settings, the combination is set to be evaluated in the phase 3 GLORA-4 study (NCT06641414). If the study proves successful, the combination could cement itself as a new standard of care (SOC) for this patient population, according to Guillermo Garcia-Manero, MD.

“Lisaftoclax is a BCL-2 inhibitor that is similar to venetoclax [Venclexta] but with a different pharmacological profile,” Garcia-Manero, the chair ad interim of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive®. “It has less drug-drug interactions and a different half-life. It may also be safer than venetoclax.”

What are the prior data that have been reported with lisaftoclax in MDS?

Lisaftoclax plus azacitidine was evaluated for the treatment of patients with relapsed/refractory MDS in a phase 1b/2 study (NCT04501120).¹ The primary end point of the trial was safety. Secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival, and overall survival.

Findings presented during the 2024 ASH Annual Meeting demonstrated that patients who received lisaftoclax at 600 mg per day in combination with azacitidine (n = 23) experienced an ORR of 73.9%, with a complete remission (CR) rate of 30.4%. The composite CR rate was 69.6%, with 52.2% of patients achieving CR and 17.4% experiencing CR with limited count recovery. Patients with higher-risk treatment-naive MDS who received the combination across dose levels of lisaftoclax (n = 40) achieved an ORR of 77.5% (95% CI, 61.5%-89.2%) and a CR rate of 25.0%.

In terms of safety, the most common grade 3 or higher hematologic treatment-related adverse effects (TRAEs) included leukopenia (71.4%), neutropenia (65.3%), thrombocytopenia (65.3%), anemia (20.4%), and febrile neutropenia (12.2%). Serious TRAEs occurred at a rate of 28.6%. Treatment delays due to AEs occurred in 22.4% of patients. Notably, no cases of tumor lysis syndrome or 60-day mortality were reported.

In another phase 1b/2 trial (NCT04964518), lisaftoclax in combination with azacitidine was evaluated for the treatment of patients with treatment-naive or venetoclax-exposed myeloid malignancies.² The study included 22 patients with relapsed/refractory higher-risk MDS/chronic myelomonocytic leukemia (CMML) and 15 patients with newly diagnosed higher-risk MDS/CMML.

Findings from the trial presented during the 2025 ASH Annual Meeting showed that efficacy-evaluable patients with newly diagnosed MDS/ CMML who received the combination (n = 15) achieved an ORR of 80.0%, including a CR rate of 40.0%. The median DOR was 11.1 months (95% CI, 1.6-not evaluable [NE]), and the median time to response (TTR) was 1.0 month (range, 1.0-4.0).

Efficacy-evaluable patients with relapsed/refractory MDS/CMLL who received lisaftoclax plus azacitidine (n = 22) had an ORR of 50.0% with a CR rate of 27.3%. The median TTR and DOR values were 1.1 months (range, 1.0-9.0) and 5.2 months (95% CI, 1.9-NE), respectively.

What are the key design features of GLORA-4?

In August 2025, Ascentage Pharma, the developer of lisaftoclax, announced that GLORA-4 received clearance from the FDA and the European Medicines Agency.³ In a news release, they noted that lisaftoclax was the only BCL-2 inhibitor to date to be evaluated in a registrational phase 3 study in higher-risk MDS globally. They also noted that the study is being conducted simultaneously in China, the US, and Europe.

GLORA-4 is a double-blind, placebo-controlled, pivotal study that is evaluating lisaftoclax plus azacitidine vs placebo plus azacitidine in newly diagnosed patients with higher-risk MDS.⁴ Key eligibility criteria include an ECOG performance status of 2 or less, an expected survival of at least 3 months, and adequate organ function.

“When we saw the results of [the phase 3] VERONA trial [NCT04401748], there was a question of whether [BCL-2 inhibition] is worth a large international trial,” Garcia-Manero said. “We believe so because we strongly believe that BCL-2 inhibition is important in this disease, hopefully with a drug that is a bit more active with a different pharmacological profile.”

Patients will be randomly assigned to receive oral lisaftoclax in combination with hypodermic or intravenous injection of azacitidine, both once daily, or azacitidine plus oral placebo. The primary end point is OS. Safety as assessed by treatment-emergent AEs and TRAEs will be evaluated as a secondary end point.

“[If GLORA-4 is successful], lisaftoclax would become the SOC worldwide, and then we would build on that,” Garcia-Manero said.

References

1. Wang H, Wei X, Liang Y, et al. Lisaftoclax (APG-2575), a novel BCL-2 inhibitor, in combination with azacitidine in treatment of patients with myelodysplastic syndrome (MDS). Blood. 2024;144(suppl 1):3202. doi:10.1182/blood-2024-205371
2. Leahy MF, Fleming S, Kropf P, et al. Phase 1b/2 study of lisaftoclax (APG-2575) combined with azacitidine (AZA) in patients (pts) with treatment-naïve (TN) or prior venetoclax (VEN)-exposed myeloid malignancies. J Clin Oncol. 2025;43(suppl 16):6505. doi:10.1200/JCO.2025.43.16_suppl.6505
3. Ascentage Pharma announces global registrational phase III study of lisaftoclax for first-line treatment of patients with higher-risk myelodysplastic syndrome cleared by US FDA and EMA. News release. Ascentage Pharma. August 17, 2025. Accessed January 22, 2026. https://www.ascentage.com/ascentage-pharma-announces-global-registrational-phase-iii-study-of-lisaftoclax-for-first-line-treatment-of-patients-with-higher-risk-myelodysplastic-syndrome-cleared-by-us-fda-and-ema/
4. Lisaftoclax (APG-2575) Combined with azacytidine (AZA) in the treatment of patients with higher-risk myelodysplastic syndrome (GLORA-4). ClinicalTrials.gov. Updated November 20, 2025. Accessed January 22, 2026. https://www.clinicaltrials.gov/study/NCT06641414