epacadostat (INCB024360) / Incyte - LARVOL DELTA

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab as first-line treatment for metastatic non-small cell lung cancer with high levels of programmed death-ligand 1: a randomized, double-blind phase 2 study. (PubMed, BMC Cancer) - P2 | "Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted."

Clinical • Journal • Metastases • P2 data • Hematological Disorders • Hypotension • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor • IDO1 • PD-L1

Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016. (PubMed, Gynecol Oncol) - "Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC."

Journal • P2 data • Gastrointestinal Disorder • Oncology • Ovarian Cancer • Pain

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study. (PubMed, BMC Cancer) - P3 | "Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted."

Clinical • Journal • Metastases • P3 data • Oncology • Solid Tumor • Urothelial Cancer • IDO1

Lipophilic Ligand Efficiency-Monitored Discovery of Potent, Achiral, and Bioavailable Apo-IDO1 Inhibitors. (PubMed, ACS Med Chem Lett) - "While the first-generation holo-IDO1 inhibitor, epacadostat, did not demonstrate sufficient response in the phase III ECHO-301 trial, multiple next-generation inhibitors and combination therapy clinical trials are ongoing...Compounds in this class have the potential for an improved pharmacodynamic response and thus are potentially attractive clinical candidates. Our lead molecules are achiral and can be easily synthesized on a large scale in several synthetic steps."

Journal • CNS Disorders • Immunology • Oncology

Durable responses to triplet immunotherapy targeting TGF-β, PD-L1, and tumor antigen, with an IL-15 receptor superagonist in mismatch repair proficient castration-resistant prostate cancer. (PubMed, J Immunother Cancer) - P1/2 | "Analyses of peripheral immune profiles provided evidence of a multifaceted antitumor immune response, including IL-15 receptor superagonist NAI-dependent expansion and activation of natural killer cells and CD8+ T cells, increased effector-to-suppressor immune cell ratios, and induction of cytotoxic immune gene programs."

Journal • Mismatch repair • pMMR • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • IL15 • PD-L1 • TGFB1

Integrated pan-cancer systems biology and structure-based simulation identifies Annona muricata-derived natural scaffolds as putative IDO1 modulators for cancer immunotherapy. (PubMed, Comput Biol Chem) - "Structure-based docking highlighted lead compounds with stronger predicted binding affinities than epacadostat, including Compound 1 (-12.3 kcal/mol) and Compound 3 (-9.5 kcal/mol)...MM-PBSA analysis further identified Compound 3 as the most energetically favorable binder (72.11 +/- 35.43 kcal mol⁻¹). Collectively, these computational findings identify Annona muricata-derived phytochemicals as promising putative IDO1-binding scaffolds, suggest testable hypotheses involving hydrophobic pocket engagement and ligand-induced conformational stabilization, and provide a focused rationale for future validation through biochemical IDO1 activity assays, kynurenine quantification, cellular target-engagement studies, and pharmacological evaluation."

IO biomarker • Journal • Oncology • IDO1

A Novel IDO1/NE Dual Inhibitor, IMM-H018 Prevents the Primary and Secondary Sepsis and Ameliorates the Kidney Injury Through Inhibiting the Cytokine Storm and Microthrombosis, and Reversing Immunosuppression. (PubMed, Adv Sci (Weinh)) - "Combined treatment with the neutrophil elastase (NE) inhibitor Sivelestat and the indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor Epacadostat showed superior efficacy to either monotherapy in LPS- and CLP-induced septic mice. In a two-hit sepsis model, IMM-H018 prevented secondary infection, enhanced bacterial clearance through improved phagocytosis, protected against renal damage, and delayed progression from acute kidney injury to chronic kidney dysfunction. These findings identify IMM-H018 as a promising therapeutic candidate for sepsis and sepsis-associated kidney injury."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Hematological Disorders • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • Thrombosis • ELANE • 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 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

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

Current applications and development of dual-target inhibitors of Ido1/TDO: From tumor immunology to neuropsychiatric disorders. (PubMed, Eur J Med Chem) - "The failure of single-target IDO1 inhibition, exemplified by the phase III setback of epacadostat, has highlighted the limitations imposed by compensatory TDO activity and the heterogeneity of the tumor microenvironment...Clinical-stage candidates have further demonstrated the translational potential of simultaneous IDO1/TDO blockade. Overall, this review offers new insights and strategic perspectives for therapeutic paradigms spanning cancer immunotherapy and neuropsychiatric intervention through modulation of the integrated immunity-metabolism-neurology axis."

Journal • Review • CNS Disorders • CNS Tumor • Mental Retardation • Oncology • Psychiatry • IDO1 • TDO2

Stage-Dependent Changes in Kynurenine Pathway Enzyme Expression Suggest Immune-Related Involvement in Bladder Cancer Progression. (PubMed, Int J Urol) - "Kyn pathway enzyme expression varies with disease progression and may indicate immune activity by influencing tumor microenvironment catabolites. BC cell sensitivity to immune stimuli differs, potentially shaping distinct immune escape mechanisms."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Immunology • Oncology • Solid Tumor • IFNG • KYNU

IDO1 inhibition enables IFNγ-elicited responsiveness of pulmonary breast cancer metastases to hypoxia-directed tumoricidal agents (AACR 2024) - "In WT (wild type) mice with established 4T1 lung metastases, administration of the IDO1 inhibitors epacadostat, navoximod or indoximod each similarly resulted in rapid collapse of the metastatic tumor neovasculature and concomitantly increased intratumoral hypoxia and sensitivity to PERK inhibition...Combining chemotherapy with immune checkpoint blockade (ICB) is recognized as an effective strategy for treating lung cancer, with first-line therapy for some patients including the alkylating agent carboplatin in conjunction with pembrolizumab...Elevated intratumoral hypoxia has also previously been linked to increased expression levels of PDL1, a favorable indicator of ICB responsiveness, and we have confirmed the upregulation of PDL1 in 4T1 lung metastases following IDO1 inhibitor administration. Our data in the lung metastasis model support future studies to evaluate whether IDO1 inhibition can be effectively combined with evofosfamide and anti-PD1 treatment to improve..."

IO biomarker • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • IFNG • IL6 • PD-L1

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 2026 ➔ Jan 2027

Trial completion date • Oncology • Sarcoma • Solid Tumor

A Phase 1/2 Randomized, Blinded, Placebo Controlled Study of Ipilimumab in Combination With Epacadostat or Placebo in Subjects With Unresectable or Metastatic Melanoma (clinicaltrials.gov) - P1/2 | N=50 | Terminated | Sponsor: Incyte Corporation | N=136 ➔ 50

Enrollment change • Melanoma • Oncology • Solid Tumor

Epacadostat with preoperative chemoradiation in locally advanced rectal cancer (LARC): Results of a translational phase I clinical trial (AACR 2024) - P1/2 | "This trial aimed to evaluate the safety of IDO1 inhibition when combined with neoadjuvant short-course radiation (SCRT) and chemotherapy with capecitabine and oxaliplatin (CAPOX) for LARC. The primary objective was to determine the recommended phase II dose (RP2D) of epacadostat for combination with SCRT and CAPOX. Epacadostat in combination with SCRT and CAPOX was well-tolerated. An NCI supported Phase 2 trial is ongoing to further evaluate the promising disease responses reported in dose escalation phase."

Clinical • IO biomarker • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor • CCL3 • IFNG • MSI • TNFA

Significance of the tryptophan catabolism pathway in triple-negative breast cancer shows potential targets in certain subsets relating to the serine pathway (AACR 2024) - "To understand the effective function of the pathway with regards to proliferation, we targeted the upper-most step of the catabolism pathway by inhibiting IDO1 with epacadostat and indoximod in different types of TNBC cell-lines and observed for changes in their growth rates via proliferation assays. Targeting the IDO1 enzyme in the kynurenine pathway shows significant correlations between the de novo serine pathway and the tryptophan catabolism pathway in TNBCs that may lead to metabolic targets conferring potential therapeutic benefits."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

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

Neoadjuvant Therapy With Iparomlimab and Tuvonralimab, Lenvatinib and Chemotherapy in Resectable ESCC (clinicaltrials.gov) - P2 | N=33 | Not yet recruiting | Sponsor: Changhai Hospital

New P2 trial • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

Epacadostat and Olaparib Synergistically Inhibit the Growth of BRCA-Proficient Triple-Negative Breast Cancer by Suppressing the Expression of BRCA1 and RAD51. (PubMed, Molecules) - "Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • IDO1 • RAD51

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 2023 ➔ Dec 2024

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

Pembrolizumab (MK-3475) Plus Epacadostat vs Standard of Care in mRCC (KEYNOTE-679/ECHO-302) (clinicaltrials.gov) - P3 | N=630 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

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 2023 ➔ Dec 2024

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

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 2022 ➔ Feb 2023

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

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: Jun 2022 ➔ Jun 2023

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

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: Jun 2020 ➔ Jul 2021

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