Background

Azacitidine plus venetoclax (AZA/VEN) improves overall survival in older or unfit patients with newly diagnosed AML, representing the standard-of-care for this patient population. However, long-term outcomes remain poor due to relapse and resistance. Upregulation of MCL-1 is a critical mechanism of resistance in AML patients treated with venetoclax. SLS009 is a highly selective Cyclin Dependent Kinase-9 (CDK9) inhibitor which leads to transcriptional suppression of MCL-1. We hypothesized that the addition of SLS009 to AZA/VEN may overcome resistance and result in meaningful clinical activity in R/R AML after previous VEN-based combinations.

Methods

This phase 2a expansion study was a dose-ranging, open-label, single-arm trial of AZA/VEN + SLS009 in R/R AML after prior Ven treatment conducted across 5 US institutions. The primary objectives of the trial were to assess efficacy, safety, tolerability, and optimal dosing regimen of SLS009 in combination with AZA/VEN. There were 3 cohorts: Cohort 3 (C3): R/R AML after prior Ven-based treatment; C4: R/R AML-MR pts with ASXL1 mutations (ASXL1m) after prior Ven-based treatment and C5: AML-MR without ASXL1m after prior Ven-based treatment. All patients were treated with SLS009 30 mg IV BIW + AZA 75 mg/m2 SQ/IV days 1-7 every 28 days and VEN 400 mg (dose-adjusted) days 1-28 every cycle. Clinical activity was assessed based on standard ELN 2022 criteria.

Results:

Forty-four pts with R/R AML and median of 2 prior treatments (range 1-8) were enrolled across all 3 cohorts (C3: n=14; C4: n=16, C5: n=14 ). The median age was 69 years (range: 24-89 years) and 26 (59%) patients were male. Most pts (59%) were non-Hispanic White. All but one patient (98%) had ELN adverse-risk AML and 41/44 (93%) were classified as AML-MR per WHO 2022 criteria. Most frequent mutations were in ASXL1 (54%), RUNX1 (37%), TP53 (27%), and SRSF2 (27%).

No dose limiting toxicities (DLTs) or treatment-related deaths were observed. Drug related toxicities of any grade occurring in ≥5% of patients across all cohorts were nausea (15%), diarrhea (20%), febrile neutropenia (7%), and thrombocytopenia (7%). Grade ≥3 drug-related AEs were rare and were most commonly febrile neutropenia (7%) and thrombocytopenia (7%).

No objective responses were observed in pts without AML-MR (n=3). Among 36 evaluable pts with AML-MR, 16 (44%) pts achieved an overall response (i.e., CR+CRi+MLFS), including 10 (29%) who achieved CR/CRi. Response rates per cohort appeared to be correlated with the median number of prior lines of therapy (mPT) : C3: 60%, (mPT: 1); C4: 40%, (mPT: 2); C5: 36%, (mPT: 3). Among evaluable pts with ASXL1m, 10/21 (48%) achieved an overall response (OR), including 19% with CR/CRi. Fifty percent (6/12) of pts with FAB M4 AML responded. Among evaluable pts with TP53m, 4/7 (57%) pts achieved a response (CR/CRi = 29%). Interestingly, 2/2 pts with MECOM rearrangements achieved an OR.

After median follow up of 3.8 months, the median survival (mOS) was 4.7 months. By cohort, mOS appeared to be correlated with mPT: C3: 8.9 months (mPT: 1): C4: NR (mPT: 2); C5: 4.8 m (mPT: 3). Across all cohorts, pts with one prior line of therapy had 58% response rate and mOS was not reached, while pts with ≥ 2 lines of prior therapy had 33% response rate and mOS of 4.4 months.

Conclusion:

Addition of SLS009 30 mg IV BIW to AZA/VEN was found to be safe and feasible without DLTs. Clinical efficacy was seen in pts with AML-MR, with a signal of activity in pts with ASXL1 mutated AML. Pts with only 1 line of ven-based prior therapy experienced the greatest benefit in terms of response and long term survival, implying a role in patients progressing after HMA + ven. A study expansion with SLS0009 plus AZA/VEN is planned in newly diagnosed AML with high-risk features.

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2025
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