eganelisib (IPI-549) / Infinity Pharma, Stelexis Biosciences - LARVOL DELTA

GAVEL: Assessing PI3K Gamma Inhibition With Azacitidine, Venetoclax and Eganelisib in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Jacqueline Garcia, MD | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

pH-Responsive liposomes co-delivering a membrane-active peptide and the PI3Kγ inhibitor to reconstruct the tumor microenvironment for enhanced antitumor immunotherapy. (PubMed, Biomater Sci) - "Here, we developed a pH-responsive and cRGD-modified multifunctional liposomal system (FP2@PSLR) to co-deliver an immunogenic cytotoxic peptide (FR) and the PI3Kγ inhibitor IPI549 for coordinated TME remodeling...Treatment resulted in significant TME reprogramming, including enhanced CD8+ T-cell infiltration, increased immune memory formation, and potent antitumor effects without systemic toxicity. These findings highlight FP2@PSLR as a rationally engineered nanoplatform capable of enhancing antitumor immunity through multi-pathway modulation of the immunosuppressive TME."

Biomarker • Journal • Hematological Disorders • Oncology • CD8 • PIK3CG

Defining Systemic and Tumor-Intrinsic Biomarkers of Immune Suppression in Renal Cell Carcinoma (KCRS 2026) - "Pharmacologic PI3Kγ inhibition (IPI-549) reprograms macrophages toward a pro-inflammatory phenotype and enhances anti-tumor immunity...These findings support the development of biomarker-guided strategies targeting macrophage-driven immune dysfunction and may inform combination therapies to improve clinical outcomes in RCC patients. Keywords RCC; biomarkers; scRNAseq; proteomics; ex vivo culture"

Biomarker • IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Renal Disease • Solid Tumor • ADGRG1 • CASP3 • CD14 • CD68 • IL10 • IL34 • IL6 • KIM1 • PIK3CG

Serglycin-ROS axis mediates synergistic lethality of PI3Kγ inhibition and Azacitidine in TP53-mutated AML. (PubMed, BMC Cancer) - "We provide the first preclinical evidence that PI3Kγ inhibition sensitizes TP53-mutated AML to AZA through a mechanism potentially involving the SRGN-ROS axis, offering a translatable combinatorial strategy for patients with this aggressive leukemia subtype."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Inflammatory Arthritis • Leukemia • Oncology • PIK3CG

Polyphosphates Attenuate Interleukin-12 Production in Macrophages Infected With Legionella pneumophila. (PubMed, FASEB J) - "However, PI3K/AKT signaling appeared to mediate polyphosphate effects, which were reversed by the PI3K inhibitors, LY294002, copanlisib, and eganelisib. Finally, long-chain polyphosphates suppressed IL-12 release also from human monocyte-derived macrophages exposed to L. pneumophila or LPS. In summary, our findings identify a selective inhibition of IL-12 by long-chain bacterial polyphosphates, suggesting that these molecules act as bacterial effectors capable of suppressing protective innate immune responses."

Journal • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases • IL12A • IL12B • IL18 • MYD88

Safety and efficacy of eganelisib in adults with higher-risk myelodysplastic syndrome (HR-MDS) or relapsed/refractory (R/R) acute myeloid leukemia (AML). (ASCO 2026) - P1 | "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 • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Solid Tumor • AKT1 • PIK3CG • TP53

Enhanced Therapeutic Efficacy of 177Lu-DOTA-tTF Combined with IPI-549 in HCC Following Incomplete IRE (SNMMI 2026) - "177Lu-DOTA-tTF specifically accumulates in post-IRE tumor areas. Combined with IPI-549, it synergistically improves HCC control by merging local radiation with immune microenvironment modulation. This theranostic strategy offers a promising approach to address residual disease after incomplete ablation."

Clinical • Hepatocellular Cancer • Solid Tumor • CD163 • PIK3CG

Stelexis BioSciences Announces Positive Phase 1 Data for Eganelisib in Relapsed/Refractory AML and Higher-Risk MDS in an Oral Presentation at ASCO 2026 (PRNewswire) - "Median overall survival (OS) was 27 weeks in PI3K-gamma-high patients vs. 9.9 weeks in low expressors (HR 0.22; 95% CI 0.07–0.75)....A modified objective response rate (defined as CR + Stable Disease with neutrophil count improvement) was achieved in: 50% (6/12) of patients with high PI3K-gamma expression vs. 0% (0/8) of patients with low PI3K-gamma expression (p<0.05, Fisher's exact test), using immunohistochemical staining of bone marrow biopsies; Responses included molecular and major cytogenetic remissions in two patients in CR....Based on these results, Stelexis plans to advance eganelisib into a randomized expansion cohort with hypomethylating agents in treatment-naïve, PI3K-gamma-high MDS patients with an IPSS-R category of intermediate, high, or very-high risk or with CMML-2."

P1 data • Trial status • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Myelodysplastic Syndrome

From IPI-549 to Novel Compounds: A Novel Strategy Integrating 3D-QSAR, Scaffold Growth, Molecular Docking, and Molecular Dynamics Simulation in PI3Kγ Inhibitor Design. (PubMed, Curr Comput Aided Drug Des) - "The present workflow provides an effective and precise approach for identifying novel PI3Kγ inhibitors and offers valuable guidance for the rational design of selective PI3Kγ- targeted therapeutics."

Journal • PIK3CG

VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation (AACR 2026) - "In the resistant models, disrupting VEGFA-VEGFR2 signaling using KDR knock-out and ramucirumab treatment restored MRTX1133 sensitivity and reversed EMT in resistant cells. Inhibition of hyperactivated PI3Kγ using eganelisib, a selective p110γ inhibitor, also replicated the same results...In a mouse xenograft model of MRTX1133-resistant PANC-1 cells, anti-VEGFR2 antibody (DC101) treatment combined with MRTX1133 rechallenge more effectively reduced tumor growth and angiogenesis than either agent alone, without significant changes in body weight...Importantly, co-targeting this axis with VEGFR2 or PI3Kγ inhibitor restored sensitivity to KRAS inhibition. These findings provide a rationale for further biomarker-guided clinical trials of combined VEGFA-VEGFR2 and KRAS inhibition in patients experiencing acquired resistance after KRAS inhibitor treatment."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KDR • KRAS • PIK3CG

OPM-116, a highly potent and specific PI3Kγ inhibitor to enhance antitumor immunity (AACR 2024) - "Tumor-associated macrophages are an integral part of the tumor microenvironment. Mario-3 phase II study safety run-in evaluating a novel triplet combination of eganelisib, atezolizumab, and nab-paclitaxel as first-line therapy for locally advanced or metastatic TNBC. AACR, Cancer Res 2021."

IO biomarker • Oncology • Triple Negative Breast Cancer • IL4 • PD-L1 • PIK3CG

Targeting of macrophage PI3Kγin prostate cancer using Eganelisib (IPI-549) reprograms immune-suppressive infiltrating macrophages to enhance anti-tumor immune responses and promote immunologically mediated tumor growth (AACR 2024) - "Altogether, these data highlight the integral role of PI3Kγ signaling in TAMs and the potential for therapeutic targeting with Eganelisib to sensitize PCa to ICB."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • PIK3CG

Highly selective and oral bioavailable PI3Kγ inhibitor for cancer immunotherapy by targeting myeloid-derived suppressor cells in tumor (AACR 2025) - "The lead PI3Kγ inhibitors were further evaluated in vivo using MC38 colon cancer model and MMTV-PyMT breast cancer model, in both monotherapy (p.o.) and combination therapy with paclitaxel (PTX) or anti-PD-1 antibody (aPD-1). The PI3Kγ inhibitors SH-315 and SH-327 demonstrated superior anti-tumor efficacy compared to IPI-549. Treatment with SH-315 and SH-327 reduced immunosuppressive MDSCs and increased cytotoxic CD8+ T cell activity, highlighting their potential to drive anti-tumor responses through targeted immune modulation and supporting their further development for cancer immunotherapy."

IO biomarker • Myeloid-derived suppressor cells • Breast Cancer • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD8 • ITGAM • PIK3CA • PIK3CB • PIK3CD • PIK3CG

Enantioselective Chiral Separation and Quantitation of PI3Kγ Inhibitor Eganelisib in Rat Plasma Using UHPLC-MS/MS: Application to Evaluate Pharmacokinetic Study. (PubMed, Chirality) - "The validated bioanalytical method was applied to evaluate the enantioselective pharmacokinetics of EGN enantiomers in rat plasma for the first time, utilizing a model-independent approach. The (R)-enantiomer showed relative fold differences in Cmax, t1/2, AUC0-t, and AUC0-∞ when compared to the (S)-enantiomer, indicating the enantioselective behavior of EGN enantiomers."

Journal • PK/PD data • Preclinical • PIK3CG

Real-Time In Vivo Visualization of Tumor-Associated Macrophage Reprogramming Using a Nitric Oxide-Activatable NIR-II Nanoinducer. (PubMed, Adv Sci (Weinh)) - "In this construct, the M2pep peptide enables M2-like TAM targeting, IPI549 reprograms them toward an M1-like phenotype while inducing NO production, and the NO-activatable NIR-II probe (ETNO) allows for in vivo visualization of macrophage repolarization via NIR-II fluorescence/photoacoustic imaging...Furthermore, combining this nanoinducer with a CD47 monoclonal antibody markedly enhanced anti-tumor immunity through M1 macrophage-mediated tumor killing and TME remodeling. This work presents an effective in vivo strategy that simultaneously facilitates and visualizes TAM repolarization, holding promise for broader applications in studying tumor initiation, metastasis, and treatment response."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

GAVEL: Assessing PI3K Gamma Inhibition With Azacitidine, Venetoclax and Eganelisib in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: Jacqueline Garcia, MD

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

PI3Kγ inhibition drives M1 macrophage differentiation and synergizes with PD-L1 blockade to improve survival in poorly immunogenic head and neck squamous cell carcinoma. (PubMed, Cancer Biol Ther) - "Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549...Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • CTLA4 • HAVCR2 • IL4 • LAG3 • PIK3CG

Defining a Targetable Leukemia Intrinsic Dependency on Noncanonical PI3Kgamma Signaling (ASH 2023) - "We conclude that inflammatory signaling-activated PIK3R5 is a biomarker for sensitivity to PI3Kγ inhibition via an unappreciated PI3Kγ-PAK1 axis. Synergy with cytarabine unmasked eganelisib sensitivity in additional leukemias, expanding the therapeutic potential of targeting PI3Kγ."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Skin Cancer • Solid Tumor • Targeted Protein Degradation • PIK3CG • SPI1

Inhibition of PI3Kγ/δ Signaling Promotes an Early Memory State in CAR T Cells and Enhances Their In Vivo Persistence and Efficacy (ASH 2024) - "We screened a library of FDA-approved drugs for those capable of enhancing TSCM in CAR T cell products and identified the PI3K gamma/delta (γ/δ) inhibitor, duvelisib (Duv), as the lead compound warranting investigation...Selective PI3Kδ inhibition with idelalisib similarly increased proportions of TSCM CAR T cells (p<0.01), while selective PI3Kγ inhibition (eganelisib) did not (p=0.48), suggesting the predominant effect of PI3Kγ/δ inhibition with Duv is mediated through PI3Kδ...Pharmacological manipulation of CAR T cells offers a safe, affordable, and rapid approach to improve CAR T cell therapy efficacy. This work provides the rationale for early phase clinical trials of Duv-treated CAR T cells for pts with R/R DLBCL."

CAR T-Cell Therapy • Preclinical • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCR7 • CD8 • IFNG • PIK3CD • PIK3CG • TCF7 • TNFA

A Phase 1b Open-Label Study to Evaluate the Safety and Tolerability of Eganelisib As Monotherapy and in Combination with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia (ASH 2024) - P1 | "Dose levels will be considered for escalation until the RDE is reached.Once the RDE of eganelisib as monotherapy and in combination with cytarabine is established, an OPT part will be initiated. All patient data from the DE part will be combined with the data from the corresponding doses at the OPT part to select the Recommended Phase 2 Dose that will be studied further.Primary endpoints are safety, tolerability, determining the RDE, and evaluating the preliminary clinical activity of eganelisib administered as monotherapy and in combination with cytarabine."

Clinical • Combination therapy • Monotherapy • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CDKN1A • PAK1 • PIK3CA • PIK3CB • PIK3CD • PIK3CG • RAC1

Immunomodulatory microbubbles targeting integrin αvβ3 in combination with immunotherapy for the theranostic of anaplastic thyroid cancer in mice. (PubMed, J Control Release) - "UTMD mediated delivery using IPI549@αIMBs combined with anti-PD1 therapy markedly inhibited subcutaneous ATC tumor growth in mice, effectively reduced the proportion of M2-like tumor associated macrophage, and increased CD8+ T cell infiltration, which alleviated the tumor immunosuppressive state. In summary, this study explored a novel therapeutic strategy for ATC, demonstrating the efficacy of the IPI549@αIMB-based UTMD approach combined with anti-PD1 therapy and validating the underlying immunomodulatory mechanisms."

Journal • Preclinical • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • CD8 • PIK3CG

Harnessing the CD16-PI3Kγ axis in peritoneal CD14hi macrophages: A transformative approach to endometriosis management. (PubMed, Int J Biol Macromol) - "Pharmacologically targeting CD16 downstream signaling, PI3Kγ inhibition via IPI-549 attenuated ESC-induced differentiation of both CD14hi and CD14low macrophages in vitro, ultimately ameliorating pathological conditions in WH-EMS mice. This cumulative evidence indicates that CD14hi macrophages promote EMS progression through CD16-dependent mechanisms. Consequently, therapeutic targeting of CD16 or its downstream effectors (e.g., PI3Kγ) represents a promising strategy for clinical EMS management."

Journal • Endometriosis • Gynecology • Women's Health • CD14 • CD80 • IL4 • PIK3CG

IPI-549 in Patients With Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Assuntina G. Sacco, MD | Recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A PHASE 1B OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF EGANELISIB AS MONOTHERAPY AND IN COMBINATION WITH CYTARABINE IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (EHA 2025) - P1 | "Importantly, knock-out of PI3K-γ or its regulatory protein encoded by PIK3R, reversed resistance to venetoclax, indicating its potential importance in combination regimens. All patient data from the DE part will be combined with the data from the corresponding doses at the OPT part to select the Recommended Phase 2 Dose that will be studied further.Primary endpoints are safety, tolerability, determining the RDE, and evaluating the preliminary clinical activity of eganelisib administered as monotherapy and in combination with cytarabine. The pharmacokinetics and pharmacodynamics of eganelisib administration will be characterized."

Clinical • Combination therapy • Monotherapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • PAK1 • PIK3CG • RAC1

TRPM2 deficiency contributes to M2b macrophage polarization via the PI3K/AKT/CREB pathway in murine sepsis. (PubMed, Innate Immun) - "The 7-day mortality rate was 92% in trpm2-/- mice, compared to 42% in IPI549-pretreated trpm2-/- mice. Moreover, IPI549-treated mice exhibited improved lung wet/dry ratios, reduced lung and liver injury scores, reversed M2b polarization and decreased bacterial load.ConclusionThe PI3K/AKT/CREB pathway mediates the effect of TRPM2 by inhibiting M2b macrophage polarization and promoting bacterial clearance during sepsis."

Journal • Preclinical • Hepatology • Infectious Disease • Liver Failure • Septic Shock