Safety, tolerability, and efficacy of mesutoclax (ICP-248) in combination with azacitidine in patients with myeloid malignancies.

Abstract

6506 Background: Venetoclax has been approved for the treatment of newly diagnosed acute myeloid leukemia (AML) in elderly or unfit pts but failed in the high-risk myelodysplastic syndromes (MDS). Mesutoclax is a novel, potent, highly selective BCL-2 inhibitor. It exhibits favorable pharmacokinetic profile without any major metabolites. Methods: ICP-CL-01205 (NCT06656494) is an ongoing, global, phase I study evaluating mesutoclax in combination with azacitidine (AZA) in pts with AML or MDS. In the dose escalation part, mesutoclax at100 mg, 125 mg, and 150 mg in combination with AZA were evaluated for safety and tolerability. 100 mg and 125 mg were selected as Recommended dose for expansion (RDE) for further evaluation. Antitumor activity in AML and MDS is assessed based on ELN 2017 and IWG 2006/2023 criteria, respectively. Herein, we report safety, tolerability and efficacy for mesutoclax with AZA in pts with AML and MDS in this phase 1 study. Results: As of January 12, 2026, a total of 59 pts were enrolled including 8 R/R AML, 39 TN AML and 12 TN MDS. The median age of AML and MDS pts was 65 (range: 23, 81) and 67 years (range: 54, 75), respectively. Adverse risk per 2017 ELN was identified in 51.1% AML pts. Azole prophylaxis and G-CSF treatment were used in 5% and 22% pts. Among the 35 evaluable TN AML pts, 30 (85.7%) achieved composite CR (cCR, CR+CRi) with central assessment of CR rate of 65.7% (23/35). Among those who achieved cCR, 86.7% (26/30) were MRD negative per flow cytometry. MRD negative in CR (CR MRD- ) was 60% (21/35). cCR was 75% in adverse risk per 2017 ELN classification. The DOR rate at 3-months was 91.7%. The 6-month OS rate was 94.1%. Among 10 response evaluable TN MDS pts, the overall response rate (ORR) per IWG 2006 criteria was 100%, including CR in 20%, marrow CR in 80%. The composite CR rate was 70% per IWG 2023 criteria including 30% CR even when most pts only received 1 cycle treatment. There were no DLT or TLS events. The most common (≥10%) grade ≥ 3 TEAEs in pooled analysis of 59 AML and MDS were neutrophil count decreased (62.7%), platelet count decreased (50.8%), anemia (33.9%), infection (16.9%), and lymphocyte count decreased (11.9%). There were 5.1% grade ≥ 3 febrile neutropenia and no TEAEs lead to dose discontinuation. SAEs were reported in 25.4% pts. For pts with TN AML, the median intervals between cycle 1 and cycle 2 initiation (requiring neutrophil ≥1*10 9 /l and platelet ≥ 100*10 9 /l) was 39 days and the median duration of grade 4 neutropenia and thrombocytopenia were 17 and 9 days, respectively. Conclusions: The combination of mesutoclax and azacitidine demonstrated a favorable safety profile and encouraging anti-tumor activity not only in AML but also in MDS pts, supporting its continued development for the treatment of myeloid malignancies. These preliminary results warrant further investigation in larger, randomized trials. Clinical trial information: NCT06656494 .