epacadostat (INCB024360) / Incyte - LARVOL DELTA

Neoadjuvant epacadostat (INCB024360) combined with short course radiotherapy in patients with locally advanced rectal cancer: Efficacy and safety from a phase 2 trial. (ASCO-GI 2026) - P1/2 | "Funded by NIH (grant number 1R01CA278197-01A1) Clinical Trial Registration Number: NCT03516708 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor

Adverse pro-tumorigenic effects of IDO1 catalytic inhibitors mediated by the non-enzymatic function of IDO1 in tumor cells. (PubMed, Front Immunol) - "By studying the turnover of IDO1 protein in human tumor cells exposed to various IDO1 catalytic inhibitors, such as epacadostat, linrodostat, and navoximod, we show here that these molecules stabilize a non-enzymatic protein conformation of IDO1, independently of their mechanism of inhibition. In the thyroid carcinoma cell line FTC-133, the stabilized and non-enzymatic IDO1 protein promotes the proliferation and migration of the tumor, resulting in an adverse pro-tumorigenic effect. These results uncover an unexpected adverse effect of IDO1 inhibitors in the tumor microenvironment that overcomes the enzymatic inhibition of IDO1, and suggest protein degradation, rather than enzymatic inhibition, as a more effective approach to target IDO1 in the tumor microenvironment."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • IDO1

Pembrolizumab Plus Epacadostat, Pembrolizumab Monotherapy, and the EXTREME Regimen in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-669/ECHO-304) (clinicaltrials.gov) - P3 | N=89 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

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

Retifanlimab and Epacadostat in Combination With Radiation and Bevacizumab in Patients With Recurrent Gliomas (clinicaltrials.gov) - P2 | N=51 | Completed | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Completed | Trial completion date: Apr 2026 ➔ Oct 2025

Trial completion • Trial completion date • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Discovery of a novel IL4I1 inhibitor by high-throughput screening of the SymeGold library (AACR-NCI-EORTC 2025) - "Although IDO1 inhibitors were tested in clinical trials to enhance immune checkpoint inhibitor efficacy, the combination of the IDO1 inhibitor epacadostat and the anti-PD1 antibody pembrolizumab failed in a phase III trial, showing no added benefit of the combination in comparison to pembrolizumab monotherapy. The hit showed no inhibition in IDO1, IDO2 and TDO biochemical assays. Analogs are being synthesized for further testing in cancer models to evaluate the therapeutic potential of IL4I1 inhibition."

Oncology • Solid Tumor • IL4 • IL4I1

IDO and TDO inhibitors in cancer immunotherapy: mechanisms, clinical development, and future directions. (PubMed, Front Pharmacol) - P1 | "Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03844438."

Journal • Review • Oncology • TDO2

Indoleamine 2,3-dioxygenase 1 inhibition reverses cancer-associated fibroblast-mediated immunosuppression in high-grade serous ovarian cancer. (PubMed, FEBS Open Bio) - "CAFs suppressed T-cell proliferation and induced PD-1 expression in CD4+ and CD8+ T cells, effects reversed by epacadostat. IDO1 inhibition enhanced T-cell proliferation via AKT signaling, restored T-cell cytotoxicity, and increased ovarian cancer cell apoptosis. These findings suggest that targeting IDO1 may help counteract CAF-mediated immunosuppression and enhance antitumor immunity in HGSOC."

IO biomarker • Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CAFs • CD4 • CD8 • IDO1 • MT-CO2 • PD-1 • PD-L1

Excessive progesterone impairs mouse decidualization via the Kyn-AhR pathway. (PubMed, Front Cell Dev Biol) - "Epacadostat (IDO1 antagonist) or RU486 (progesterone receptor antagonist) effectively block P4-induced Kyn elevation. Additionally, nucleolar size in stromal cells is increased both in vivo and in vitro following excessive P4 treatment. Our findings suggest that excessive P4 impairs mouse decidualization via the Kyn-AhR pathway."

IO biomarker • Journal • Preclinical • BMP2 • CYP1A1 • CYP1B1 • IDO1 • TDO2

Reprogramming Immune Escape: development of Apo-IDO1 Inhibitors with improved Metabolic Stability (CICON 2025) - "Due to epacadostat's (holo-IDO1 inhibitor) failure, focus has shifted to apo-IDO1 inhibition, for this reason, in collaboration with Professor Pirali's laboratory, we identified VS-13, a potent apo-IDO1 inhibitor (IC50= 16 nM), through virtual screening approaches...Notably, HLM assays revealed substantially higher residual compound levels compared to MLM, indicating improved metabolic profiles in the human system. Two analogues exhibited an optimal balance between potency and metabolic stability, with IC50values of 116 nM and 126 nM, and HLM stability (residual compound after one hour) of 90% and 97%, respectively."

IO biomarker • Melanoma • Solid Tumor

Low Indoleamine 2,3-Dioxygenase 1 Expression Enhances Dendritic Cells Response to Tumor Cells Against Hepatocellular Carcinoma. (PubMed, J Hepatocell Carcinoma) - "In vivo, a subcutaneous xenograft tumor model of nude mice was established by subcutaneously inoculating SK-HEP1 and treated with IDO1 catalytic inhibitor epacadostat (EPA) to observe the effect of IDO1 on tumor growth and immune cells infiltration...Targeting IDO1 may represent a promising immunotherapeutic strategy. However, its immunomodulatory effects must be validated in immunocompetent or humanized animal systems before clinical translation."

IO biomarker • Journal • Fibrosis • Hepatocellular Cancer • Immunology • Oncology • Solid Tumor • IDO1

Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner. (PubMed, Commun Chem) - "A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells."

IO biomarker • Journal • Oncology • IDO1

Indoleamine 2,3-dioxygenase 1 in cancer immunotherapy: from small-molecule inhibition to PROTAC-mediated degradation. (PubMed, Front Pharmacol) - "The therapeutic landscape of IDO1 inhibition has progressed significantly from early heme-competitive inhibitors like epacadostat to next-generation proteolysis-targeting chimera (PROTAC) technology...This review systematically evaluates: (1) clinically investigated IDO1 inhibitors and their pharmacological profiles, and (2) the preclinical promise of IDO1-targeting PROTAC degraders. Through critical analysis of their mechanisms of action and therapeutic potential, we provide insights into optimizing IDO1-targeted strategies for cancer immunotherapy."

IO biomarker • Journal • Review • Oncology • Targeted Protein Degradation • IDO1

IDO-1 Promotes Pulmonary Vascular Remodeling Via Kynurenine Pathway in Pulmonary Arterial Hypertension. (PubMed, J Am Heart Assoc) - "Increased IDO-1 expression in peripheral blood mononuclear cells may drive KP activation and promote pulmonary vascular remodeling in PAH. Epacadostat prevents the development of monocrotaline-induced PH. These findings suggest a novel approach for the treatment of PAH."

IO biomarker • Journal • Cardiovascular • Hypertension • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • IDO1

Pembrolizumab (MK-3475) Plus Epacadostat vs Standard of Care in mRCC (KEYNOTE-679/ECHO-302) (clinicaltrials.gov) - P3 | N=129 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

Trial completion • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Design, Synthesis, and Biological Evaluation of Novel Hydroxyamidine Derivatives as Indoleamine 2,3-Dioxygenase 1 Inhibitors. (PubMed, ACS Med Chem Lett) - "The results indicated that compounds I-1 and I-2 exhibited activity similar to that of Epacadostat in inhibiting recombinant hIDO1 and hIDO1 expression in HeLa cells...The physicochemical properties along with pharmacokinetic profiles of both compounds were also predicted, and they were found to possess favorable characteristics. The active compounds developed in this research may serve as valuable references for discovering highly effective IDO1 inhibitors."

IO biomarker • Journal • Lung Cancer • Oncology • Solid Tumor • IDO1

Expression of indoleamine-2,3-dioxygenase 1 in sebaceous glands and related tumors of the eyelid: a potential diagnostic target. (PubMed, Orbit) - "Prior to these findings, clinical management centered around surgical excision. The use of molecular compounds such as indoximob, epacadostat, BMS-986205 and navoximod, that directly target IDO1 opens new possibilities for targeting these tumors, improving clinical outcomes, and minimizing the morbidities often associated with surgery."

IO biomarker • Journal • Eye Cancer • Oncology • IDO1

POD1UM-204: Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy. (clinicaltrials.gov) - P2 | N=206 | Active, not recruiting | Sponsor: Incyte Corporation | Trial primary completion date: Apr 2025 ➔ Apr 2026

dMMR • MSI-H • Trial primary completion date • Endometrial Cancer • Oncology • Solid Tumor • MSI • PD-L1 • POLE

Safety and efficacy of pembrolizumab and epacadostat combination therapy in metastatic epithelial-derived cancers: A systematic review and meta-analysis of randomized controlled trials. (ASCO 2025) - "Our analysis of the seven RCTs showed no statistically significant benefit of Pembrolizumab + Epacadostat in reducing all-cause mortality, complete response rate, partial response, objective response rate, stable disease, treatment related SAE, Grade≥3 AE, SAE, discontinued study drug due to TAE, treatment related AE, Grade≥3 AE treatment related or progressive disease compared to the control. These findings suggest limited therapeutic advantage of this combination, highlighting the need for further research."

Combination therapy • IO biomarker • Metastases • Retrospective data • Review • Oncology • IDO1 • PD-L1

Phase II study of epacadostat (INCB024360) added to preoperative chemoradiation in patients with locally advanced rectal cancer. (ASCO 2025) - P1/2 | "We aim to enroll 27 patients in the treatment cohort and 10 in the biomarker cohort. Clinical Trial Registration: NCT03516708"

Clinical • IO biomarker • Metastases • P2 data • Colorectal Cancer • Microsatellite Instability • Oncology • Rectal Cancer • Solid Tumor • MSI

Neovascular pruning by IDO1 inhibitors can potentiate immunogenic cytotoxicity of ischemia-targeted agents to synergistically enhance anti-PD-1 responsiveness. (PubMed, J Immunother Cancer) - "Improving therapeutic outcomes for patients with lung tumors, arising either as primary lesions or metastatic colonies, is of vital clinical importance. Building on preclinical evidence for IDO1's role in promoting inflammatory neovascularization of lung tumors, this study demonstrates how the intratumoral ischemic stress elicited by IDO1 inhibition can potentiate the immunogenic cytotoxicity of ischemia-targeted agents to effectively leverage immune checkpoint blockade responsiveness to confer a synergistic survival benefit. These findings provide a novel perspective on how IDO1 inhibitors can impact tumor biology and open up new possibilities for therapeutic applications."

IO biomarker • Journal • Breast Cancer • Cardiovascular • Lung Cancer • Oncology • Solid Tumor • IFNG • PERK

A TCR nanovesicle antibody for redirecting T cells and reversing immunosuppression as a tumor immunotherapy strategy. (PubMed, J Control Release) - "Furthermore, epacadostat, an inhibitor of indoleamine 2,3-dioxygenase, can be loaded into TPC NV to suppress regulatory T cell (Treg) generation and enhance dendritic cell (DC) maturation by inhibiting tumor tryptophan metabolism. This dual action amplifies adaptive immune activation and triggers a robust systemic anti-tumor immune response."

Journal • Oncology • Solid Tumor

A Study of Epacadostat, an IDO1 Inhibitor, in Combination With Pembrolizumab in Patients With Metastatic and/or Locally Advanced Sarcoma (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial primary completion date: Jan 2026 ➔ Sep 2024

Trial primary completion date • Oncology • Sarcoma • Solid Tumor

Compensatory interactions between tryptophan catabolism and serine metabolism highlight potential vulnerabilities in TNBC cells with dysregulated de novo serine synthesis (AACR 2025) - "IDO1 inhibitor (Epacadostat), PHGDH inhibitor, and SHMT inhibitor (SHIN1) were used to inhibit tryptophan catabolism, de novo serine synthesis, and folate cycle, respectively... Our findings show serine and tryptophan metabolism are tightly co-regulated in TNBC cells. It also highlights the heterogeneity and complexity of how these cells utilize varying metabolic pathways to achieve these compensatory interactions. Our data supports that certain TNBC cells with dysfunctional de novo serine synthesis may be vulnerable to strategies that leverage their limited capacity to compensate between these pathways."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PHGDH • SHMT1

L-Kynurenine activates the AHR-PCSK9 pathway to mediate the lipid metabolic and ovarian dysfunction in polycystic ovary syndrome. (PubMed, Metabolism) - "Additionally, letrozole (LET) induced PCOS-like mice displayed increased hepatic L-Kyn levels. Mechanistically, both in vivo and in vitro experiments demonstrated that the upregulation of indoleamine 2,3-dioxygenase (IDO1) activates the aryl hydrocarbon receptor (AHR) - proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway in the liver of PCOS-like mice, thereby contributing to dyslipidemia. Treatment with epacadostat, an inhibitor of the enzyme IDO1, or PLP, a cofactor for L-Kyn catabolism, effectively restored ovarian function, improved glucose tolerance, and ameliorated lipid profile abnormalities in PCOS-like mice."

Journal • Dyslipidemia • Metabolic Disorders • Polycystic Ovary Syndrome • IDO1

Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting IDO-Mediated Tryptophan Metabolism. (PubMed, Cancer Sci) - "Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab-resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • CD8 • IDO2 • IFNG