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.

6505 Background: Lisaftoclax (LISA), an investigational, orally active small molecule BCL-2 inhibitor, has shown enhanced treatment responses when combined with AZA in preclinical and clinical studies. We evaluated the safety and efficacy of LISA plus AZA in pts with myeloid malignancies. Methods: This open-label, multicenter study enrolled pts with TN or relapsed/refractory (R/R) AML/MPAL or high-risk (HR) MDS/CMML. Prior VEN treatment was permitted. In Part 1, LISA was administered at escalating doses (200, 400, 600, or 800 mg once daily [QD]) and combined with AZA to assess DLTs and determine the MTD. Part 2 evaluated the safety and efficacy of LISA 200, 400, or 600 mg QD over 28 or 14 days of 28-day cycles, combined with AZA at the standard dose (75 mg/m 2 on days 1-7 or 1-5 and 8-9 of each cycle). Safety and efficacy assessments were conducted for all pts receiving at least one dose of LISA. Results: As of January 6, 2025, 97 pts were enrolled, with a median treatment duration of 2 (0-16) cycles. Pt distribution included: 49 R/R AML; 20 R/R HR-MDS; 14 TN HR-MDS; 7 TN AML; 4 R/R CMML; 2 R/R MPAL; and 1 TN CMML. The median (range) age was 71 (23-89) years, with 59.8% of pts being male and 73.2% having an ECOG PS ≥ 1. Pts with R/R AML/MPAL D1-28, D1-14, and MDS/CMML had median prior therapies of 2.0 (1.0-8.0), 1.0 (1.0-3.0), and 1.0 (1.0-2.0), respectively, with prior VEN exposure in 46.2% (12/26), 50.0% (5/10), and 14.3% (2/14), respectively. There were no DLTs, and the MTD was not reached. The RP2D for TN HR-MDS was AZA (standard dose) + LISA 600 mg on days 1-14; for TN AML, it was AZA (standard dose) + LISA 600 mg on days 1-28. Common grade 3/4 TEAEs included neutropenia (40%), febrile neutropenia (31%), and thrombocytopenia (22%). Others included sepsis (9%), pneumonia (7%), and lower-respiratory-tract infections (3%). Febrile neutropenia was the most frequently reported SAE (26.8%). Only 3% of pts had neutropenia leading to a dose reduction of LISA, with no 60-day mortality reported. In 14 efficacy-evaluable pts with TN-MDS/CMML, the ORR was 64%, with CR and marrow CR achieved by 29% and 36% of pts, respectively; no PRs were observed. In pts with R/R AML treated with LISA for either 28 (n = 18) or 14 days (n = 8) of repeated 28-day cycles, the ORRs were 39% and 50%, respectively, including CR rates of 28% and 37.5%, respectively. In 20 pts refractory to VEN, the ORR was 17% (3/18) in pts with AML/MPAL and 50% (1/2) in pts with HR-MDS; 11% of pts with AML/MPAL and 50% with MDS had bone marrow blasts < 5%. Conclusions: LISA at different dose regimens combined with AZA provides promising treatment options for pts with HR-MDS or AML. No DLTs occurred. The MTD was not reached. The combination was efficacious and well tolerated, with few dose modifications and low infection rates, supporting further clinical development of this regimen in these populations (APG2575AU101; NCT04964518). Clinical trial information: NCT04964518 .