Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor, in Combination with Azacitidine in Treatment of Patients with Myelodysplastic Syndrome (MDS)

I ntroduction Hypomethylating agents (HMAs) remain the standard of care in MDS. In the event of HMA failure/resistance, new therapeutic options are needed. Preclinical data have shown that novel, investigational BCL-2 inhibitor lisaftoclax synergistically induces apoptosis when combined with an HMA. Here, we present follow-up safety and efficacy data from a phase 1b/2 clinical trial evaluating lisaftoclax combined with azacitidine in adults (≥ 18 years) with MDS. Methods Patients with higher-risk MDS (IPSS-R score > 3.5; blasts > 5%), including those with treatment-naïve (TN) or relapsed or refractory (R/R) disease, were enrolled. Lisaftoclax alone at an assigned dose (400, 600, or 800 mg) was administered orally once daily from Days 1 to 14 and combined with azacitidine (75 mg/m2/day) on Days 1 to 7 in repeated 28-day cycles. A daily ramp-up was used before the first cycle to prevent tumor lysis syndrome (TLS). The primary objectives of the study were to assess the efficacy and safety of this combination in patients with MDS and establish the recommended phase 3 dose for lisaftoclax. Complete response (CR) and marrow CR rates were evaluated in accordance with 2006 International Working Group (IWG) criteria. Results As of July 1, 2024, a total of 49 patients were enrolled: 8 had R/R MDS (lisaftoclax 600 mg [n = 5] and 800 mg [n = 3]) and 41 had TN MDS (lisaftoclax 400 mg [n = 16], 600 mg [n = 16], and 800 mg [n = 2]). The median (range) age was 66 (22-83) years, and 55.1% of patients were male. IPSS-R risk categories were as follows: intermediate (12/49 [24.5%]), high (24/49[49.0%]), and very high (13/49 [26.5%]). Among 39 patients with genetic mutational profile data, 9 (23.1%) had TP53 mutations; 11 (28.2%), TET2 mutations; 10 (25.6%), ASXL1 mutations; and 10 (25.6%), RUNX1 mutations. At baseline, 70.8% (34/48) of patients reported grade ≥ 3 anemia; 54.2% (26/48), grade ≥ 3 neutropenia; and 45.8% (22/48), grade ≥ 3 thrombocytopenia. All patients treated with lisaftoclax combined with azacitidine reported treatment-emergent adverse events (TEAEs), of which 93.8% were grade ≥ 3 AEs and 35.4% serious AEs. Common grade ≥ 3 nonhematologic TEAEs (≥ 10% incidence) included pneumonia (24.4%) and hypokalemia (10.2%). Common grade ≥ 3 hematologic TEAEs included leukocyte count decreased (75.5%), neutropenia (69.4%), thrombocytopenia (65.3%), anemia (24.5%), and febrile neutropenia (18.4%). Grade ≥ 3 infections (system-organ-class) were reported in 46.9% of patients, of which 26.5% were treatment related. Treatment delays between cycles due to AEs occurred in 11 (22.4%) patients, with a median delay time (range) of 12 (1-63) days. A total of 95.9% of patients reported treatment-related adverse events (TRAEs), of which 87.8% were grade ≥ 3 AEs and 28.6% serious AEs. Common grade ≥ 3 hematologic TRAEs included leukocyte count decreased (71.4%), neutropenia (65.3%), thrombocytopenia (65.3%), anemia (20.4%), and febrile neutropenia (12.2%). Lisaftoclax dose reduction occurred in 4 (8.2%) patients. Neither 60-day mortality nor TLS was reported. In 8 patients with R/R MDS, the median (range) duration of treatment (DOT) was 3.2 (1.2-9.4) months. The overall response rate (ORR = CR [12.5%] + marrow CR [62.5%]) was 75.0% (95% CI, 34.9-96.8). In 40 efficacy-evaluable patients with TN MDS, the median DOT (range) was 4.5 (0.5-12.1) months; the ORR rate, 77.5% (95% CI, 61.5-89.2); and the CR rate, 25.0% per IWG 2006 criteria. Furthermore, the ORR and CR rates in 23 patients with TN MDS receiving lisaftoclax 600 mg combined with azacitidine were 73.9% and 30.4%, respectively; because these patients had a relatively longer median DOT (6.01 months), we conducted further analyses per IWG 2023 criteria. The composite CR rate (CR2023 = CR [52.2%] + CRL [17.4%]) was 69.6%, and the median time to CR (range) was 2.84 (1.1 - 8.7) months. Both the median progression-free survival and overall survival rates were not reached. Conclusions The clinical data support an emerging role for lisaftoclax in combination with azacitidine for treatment of patients with higher-risk TN or R/R MDS. This combination therapy was efficacious and well tolerated, resulting in no 60-day mortality, few dose modifications, and low infection rates, supporting further clinical development of this combination in patients with higher-risk MDS. Internal study identifier: APG2575AC101. Clinicaltrials.gov identifier: NCT04501120.