Safety and efficacy of eganelisib in adults with higher-risk myelodysplastic syndrome (HR-MDS) or relapsed/refractory (R/R) acute myeloid leukemia (AML).

6507 Background: The gamma isoform of PI3K (PI3Kγ) directs a myeloid-specific signaling node (PI3Kγ-AKT1-PAK1) identified as a core dependency in AML responsible for LSC self-renewal, medullary homing, and resistance to venetoclax and nucleoside analogues (Luo 2024; Gu 2024; Kelly 2024; Qiu 2025). Eganelisib is a highly potent isoform-specific inhibitor of PI3Kγ that demonstrated safety and effective target modulation in solid tumors. Here we report results of a Phase I study of eganelisib monotherapy in R/R AML or HR-MDS using doses previously shown to be biologically active [NCT06533761]. Methods: Eligible patients had ECOG PS <2, R/R AML or IPSS-R Int-Very High risk MDS that was R/R to prior therapy with ≥10% BM blasts. Eganelisib was administered orally in two cohorts of 45 mg and 60 mg QD in 28-day cycles. The primary endpoints were safety and efficacy per ELN 2022 (AML) and IWG 2023 (HR-MDS) and recommended dose for expansion (RDE). Additional endpoints included PK and PD effects assessed by AKT S273 phosphorylation in monocytes. Results: 15 patients have been treated to date (n=7, 45 mg; n=8, 60 mg); patient characteristics are summarized in the table below. There were no DLTs at either dose level. PD studies revealed dose-dependent reduction in AKT phosphorylation of ~90% at the 60 mg dose. Of the 10 patients who completed a 28-day cycle, anti-leukemic activity and evidence of clinical benefit was observed in 4 patients, including a CR in 1 patient at 45 mg. Three patients at 60 mg demonstrated anti-leukemic activity: 1 patient achieved <5% bone marrow blasts by flow cytometry, major cytogenetic response, rapid subclonal clearance, with full trilineage count recovery and low levels of persistent circulating blasts; two patients (both with TP53 mutations) with stable/decreasing marrow blasts had a progressive rise in neutrophils while on therapy. Longest duration of treatment is 5 cycles. Exposure to eganelisib was variable across both dose levels, and both doses showed overlapping plasma concentrations. Conclusions: Eganelisib demonstrates effective inhibition of PI3Kγ with single agent activity in heavily treated, poor-risk patients, validating PI3Kγ as a key vulnerability in MDS and AML. Importantly, eganelisib had no intrinsic hematologic toxicity, consistent with previous studies and pre-clinical observations that PI3Kγ is dispensable for normal hematopoiesis. Given the capacity to potentiate activity of nucleoside analogues and venetoclax, combined therapy in previously untreated HR-MDS & AML patients at the RDE of 60 mg QD is planned. Clinical trial information: NCT06533761 . 45 mg (n=7) 60 mg (n=8) All (n=15) Age (median/range) 78 (71-85) 59 (20-74) 72 (20-85) AML | MDS 7 | 0 7 | 1 14 | 1 Prior MDS or MDS-related changes 6 5 10 Prior therapies(median/range) 2 (1-3) 2 (1-6) 2 (1-6) Adverse-risk ELN 86% 71% 79% TP53 mutation 43% 43% 43% Prior intensive chemo/venetoclax 14%/71% 50%/100% 33%/87%