epacadostat (INCB024360) / Incyte - LARVOL DELTA

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

Electrochemical Analysis and Inhibition Assay of Immune-Modulating Enzyme, Indoleamine 2,3-Dioxygenase. (PubMed, Pharmaceuticals (Basel)) - "A well-known inhibitor of hIDO, epacadostat, hindered this catalytic signal according to its concentration, demonstrating the rapid evaluation of its inhibition activity for the hIDO reaction. Through an in silico study using the proposed electrochemical assay system, we discovered a strong inhibitor candidate with a half-maximal inhibitory concentration of 10 nM. An accurate and rapid assay system in drug discovery for hIDO and kynureine pathway-targeted immunotherapy has been developed."

Journal • Oncology

Pembrolizumab (MK-3475) Plus Epacadostat vs Standard of Care in mRCC (KEYNOTE-679/ECHO-302) (clinicaltrials.gov) - P3 | N=129 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Feb 2025 ➔ Jun 2025

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

IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment. (PubMed, J Transl Med) - "Targeting IDO1 represents a promising strategy to overcome immunosuppressive barriers in gastrointestinal cancers, improving the efficacy of CLDN18.2-CAR-T therapy. These findings highlight the potential for integrating IDO1 inhibition into CAR-T treatment regimens to address resistance in treatment-refractory cancers."

Biomarker • IO biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CLDN18

Polypharmacology of carbonic anhydrase inhibitors and activators. (PubMed, Expert Opin Pharmacother) - "Several antiepileptics (topiramate, zonisamide, lacosamide, levetiracetam), some atypical antipsychotics (sulpiride, veralipride), celecoxib, polmacoxib, pazopanib, the antiulcer agent famotidine and compounds in clinical trials (epacadostat and PCI-27483) as antitumor agents significantly inhibit several CA isoforms of the 15 human ones, apart their action on several other targets...Polypharmacology involving CA inhibitors/CAAs are understood from the chemical, structural and pharmacological viewpoints. The many other drug targets with which these modulators of activity interact allow for de novo design of such agents for the management of multifactorial conditions in need of innovative drugs."

Journal • Review • CNS Disorders • Epilepsy • Genetic Disorders • Glaucoma • Obesity • Oncology • Ophthalmology

Cooperative Hedgehog/GLI and JAK/STAT signaling drives immunosuppressive tryptophan/kynurenine metabolism via synergistic induction of IDO1 in skin cancer. (PubMed, Cell Commun Signal) - "These results identify the immunosuppressive IDO1-kynurenine pathway as a novel pro-tumorigenic target of oncogenic GLI and STAT1/STAT3 cooperation. Our data suggest simultaneous pharmacological targeting of these signaling axes as rational combination therapy in melanoma and non-melanoma skin cancers."

IO biomarker • Journal • Basal Cell Carcinoma • Genetic Disorders • Non-melanoma Skin Cancer • Skin Cancer • Solid Tumor • GLI1 • IDO1 • IFNG • IL6 • STAT1

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 completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Oncology • Sarcoma • Solid Tumor

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 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Dec 2024 ➔ Dec 2025

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

HDACi combination therapy with IDO1i remodels the tumor microenvironment and boosts antitumor efficacy in colorectal cancer with microsatellite stability. (PubMed, J Nanobiotechnology) - "The combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials."

Biomarker • Combination therapy • IO biomarker • Journal • Tumor microenvironment • Colorectal Cancer • Oncology • Solid Tumor • CD8

Epacadostat Before Surgery in Treating Patients With Newly Diagnosed Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Surgery • Trial completion • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • IDO1

Comparison on the effectiveness of multiple single and double immunotherapy treatments on advanced angiosarcoma patients: Meta analysis & systematic review (ESMO-IO 2024) - "Studies were extracted and evaluated based on inclusion (Accessible full text, Randomized Controlled Trial, Clinical Trials, and last 5 years) and exclusion criterias (non-english text, animal studies, case report, systematic reviews, and meta analysis) The quality of included studies were further assessed using Newcastle-Ottawa Scale (NOS).Results Seven studies consisting of RCTs and clinical trials were included, screening a total of 195 patients. Among the seven studies, bempegaldesleukin + nivolumab yields 0.60 (95% Cl; 0.08-4.40; P < 0.00001), epacadostat + pembrolizumab yields 0.03 (95% Cl; 0.00-0.29; P < 0.00001), ipilimumab + nivolumab yields 0.33 (95% Cl; 0.07-1.49; P < 0.00001), pembrolizumab alone yields 3.33 (95% Cl; 0.36-30.70; P < 0.00001), and Immune checkpoint inhibitors (ICIs) yields 0.13 (95% Cl; 0.02-0.71; P < 0.00001) Adverse effect wise is 17.00 (95% Cl; 0.74-391.68; P < 0.00001), 0.30 (95% Cl; 0.10-0.92; P < 0.00001), 3.00 (95%..."

Metastases • Retrospective data • Review • Angiosarcoma • Oncology • Sarcoma • Solid Tumor

A phase II study of retifanlimab (PD-1 inhibitor) and epacadostat (IDO1 inhibitor) in combination with bevacizumab and hypofractionated radiotherapy for recurrent glioblastoma: NCT03532295 (SNO 2024) - P2 | "Key inclusion criteria included dexamethasone ≤ 4 mg/day. Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders."

Combination therapy • IO biomarker • P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Malignant Glioma • Oncology • Solid Tumor • IDH1 • IDH2 • MGMT

EXPRESSION OF TRANSPOSABLE ELEMENTS AND IKZF1 PREDICTS IMMUNE INFILTRATES IN SARCOMAS AND CORRELATES WITH OUTCOMES AFTER IMMUNE CHECKPOINT INHIBITION (CTOS 2024) - "Here, we update these findings to include analysis of additional cohorts, sarcoma subtype-specific data, on-treatment biopsies, and additional clinical outcome measures We retrospectively analyzed RNA-seq data from our initial cohort of 67 sarcoma patients representing 12 subtypes who were treated on ICI clinical trials (pembrolizumab plus talimogene laherparepvec, nivolumab plus bempegaldesleukin, and pembrolizumab plus epacadostat) including 46 paired pre- and on-treatment biopsies. We identify tumor-intrinsic features that contribute to tumor immune phenotypes, focusing on expression of epigenetic regulators and TEs, which are normally epigenetically silenced and can stimulate inflammatory signaling. In an initial heterogeneous cohort of sarcoma patients treated with ICI, we found that TE and IKZF1 expression predicted immune infiltrates, correlated with PFS, expression of inflammatory pathways, and increased in tumors which gained immune infiltrates during ICI..."

Biomarker • Checkpoint inhibition • IO biomarker • Leiomyosarcoma • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • IKZF1 • STING

A phase II study of retifanlimab (PD-1 inhibitor) and epacadostat (IDO1 inhibitor) in combination with bevacizumab and hypofractionated radiotherapy for recurrent glioblastoma: NCT03532295 (SNO 2024) - P2 | "Key inclusion criteria included dexamethasone ≤ 4 mg/day. Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders."

Combination therapy • IO biomarker • P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Malignant Glioma • Oncology • Solid Tumor • IDH1 • IDH2 • MGMT