Eganelisib is a first-in-class, oral, highly selective PI3Kγ inhibitor with strong gamma isoform affinity. Prior solid tumor studies showed well-tolerated daily dosing (30–60 mg) with consistent target modulation and no significant myelosuppression. In myeloid malignancies, PI3Kγ signaling reinforces the differentiation block in AML and higher-risk MDS via PAK1, making it a key therapeutic target where inhibition can restore myeloid differentiation without intrinsic myelosuppression or lymphoid toxicity.

 

At ASCO 2026, results from an ongoing Phase I study of eganelisib monotherapy in relapsed/refractory AML and higher-risk MDS highlighted safety, pharmacodynamics, and early anti-leukemic activity. The study enrolled a heavily pretreated high-risk population, including 29% TP53-mutated/deleted, 90% abnormal cytogenetics, 76% with >2 prior therapies, and 76% prior venetoclax exposure.

Efficacy:

• mORR 50% (6/12) in PI3K-γ high vs. 0% (0/8) in low expressors (p < 0.05) 

• Responses included CRs with molecular + cytogenetic remissions 

• Rapid neutrophil recovery in responders; normalization in multiple patients 

• Activity consistent with myeloid differentiation 

• Median OS: 27 weeks (high) vs. 9.9 weeks (low); HR 0.22 (95% CI 0.07–0.75) 

• Supports PI3K-γ as a predictive biomarker and adverse prognostic factor under standard therapy.

Safety:

• Eganelisib was well tolerated at both dose levels (45 mg and 60 mg, once daily) with no dose-limiting toxicities and no intrinsic hematologic toxicity.

• AEs mainly disease-related, low-grade 

• No treatment-related SAEs 

• No Grade 5 treatment-related adverse events 

• No discontinuations due to treatment-related AEs 

• Safety consistent with myeloid-restricted PI3K-γ expression and preserved normal hematopoiesis.

Based on these findings, Stelexis plans to advance eganelisib into a randomized expansion cohort with hypomethylating agents in treatment-naïve, PI3Kγ-high MDS patients with intermediate, high, or very-high IPSS-R risk or CMML-2.

KOL insights

“The preliminary data generated by eganelisib in patients with heavily pretreated AML and higher-risk MDS is encouraging. In addition to a favorable safety and tolerability profile, Stelexis has observed evidence of biologic and clinical activity for eganelisib in a particularly difficult-to-treat patient population. I am especially delighted that Stelexis has identified a biomarker that may be used to identify patients most likely to benefit from treatment with eganelisib. These clinical data suggest that eganelisib has the potential to be effective across multiple hematologic malignancies of high unmet need.” –Expert Opinion

“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 higher-risk-MDS and AML patients at the recommended dose for expansion of 60 mg once daily is planned.”–Expert Opinion

Conclusion- AML remains a challenging and evolving treatment landscape, driven by high unmet need, especially in relapsed/refractory and higher-risk MDS populations where outcomes remain poor despite advances in targeted therapies and venetoclax-based regimens. Current treatment approaches have improved survival in some subsets, but resistance, relapse, and limited durability continue to define the competitive landscape.

Within this context, eganelisib introduces a differentiated mechanism targeting PI3Kγ, a lineage-restricted vulnerability uniquely essential for AML cell survival. By combining direct anti-leukemic effects with immune microenvironment modulation, it represents a novel therapeutic angle beyond conventional cytotoxic and targeted approaches.

Early clinical data demonstrate favorable tolerability, sustained pathway inhibition, and signs of myeloid differentiation with hematologic recovery in heavily pretreated patients, alongside biomarker-driven efficacy signals. Collectively, this positions eganelisib as a potential next-generation, biology-driven therapy that could complement or differentiate from existing AML treatment strategies in a highly competitive and rapidly evolving space.