epacadostat (INCB024360)

P2, N=41, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed

In summary, our study elucidated the effects of DSP-0509 on immune activity within the tumor microenvironment. These findings provided valuable insights that pave the way for the development of novel combination immunotherapy strategies.

These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO)...RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment.

P2, N=206, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=300 --> 206

IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment...Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment.

After disappointing results of the epacadostat as a selective IDO inhibitor in phase III clinical trials, there is much interest in the development of the TDO selective inhibitors. In addition, furo[2,3-c]pyridine-2,3-diamine was found as a common fragment for inhibition of the both targets and can be used in the design of the dual target inhibitors of the IDO and TDO. The new fragments introduced here can be a useful building blocks for incorporation into the selective TDO or dual IDO/TDO inhibitors.

Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination.

Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC.

Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted.

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.

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.

P2, N=14, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Mar 2024

P2, N=41, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2024 --> Aug 2024

Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.

P2, N=1, Terminated, Columbia University | Completed --> Terminated; Study ended prematurely at the request of the funding sponsor.

P2, N=51, Active, not recruiting, Washington University School of Medicine | Trial primary completion date: Apr 2024 --> Jul 2024

P1/2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=113 --> 53

The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC.

P1, N=17, Active, not recruiting, National Cancer Institute (NCI)

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=30, Terminated, Incyte Corporation | Trial completion date: Jun 2024 --> Jan 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2024 --> Jan 2024; Business Decision. No safety concerns contributed to this decision.

Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.

P3, N=89, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2023 --> Dec 2024

P2, N=40, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2023 --> Dec 2024

P1/2, N=113, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.

P2, N=30, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=45 --> 30

The quantitative method was validated according to FDA, ICH and EMA guidelines, later applied: i) to assess the impact of selective inhibition of hIDO1 or hTDO (human tryptophan 2,3-dioxygenase) on the kynurenine pathway in A375 (melanoma), MDA-MB-231 (breast cancer), and U87 (glioblastoma) cell lines using multivariate analysis (MVA); ii) to determine the IC values of both well-known (i.e., epacadostat, linrodostat) and the novel hIDO1 inhibitor (i.e., BL5) in the aforementioned cell lines. The proposed LC-MS/MS method is reliable and robust. Furthermore, it is highly versatile and suitable for applications in the preclinical drug research and in vitro assays.

P2, N=300, Recruiting, Incyte Corporation | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Aug 2023 --> Apr 2025

P2, N=14, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Sep 2024

Our pre-clinical study suggests that epacadostat is a candidate HCC immuno-preventive agent to be considered for early clinical testing in NAFLD patients at risk of developing HCC.

Methods This is a cohort study performed at Karolinska University Hospital in Sweden including 98 subjects with advanced CMM (M1a-d), who received anti-PD1 alone (n=88), anti-PD1+ epacadostat (clinical trial, n=3) or ipilimumab + nivolumab (n=8) as 1st line therapy in most cases (85%). Conclusions Patients developing a GC-irAE had significantly increased PFS and OS compared to the other patients. Further studies on potential biomarkers for risk of developing hypophysitis are warranted to timely avoid serious complications.

The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities with few grade 3 toxicities; produced stable disease in 33% of patients. The PK of SE results were consistent with reports that E accumulates upon repeat administration in a dose-proportional fashion with E levels observed across the three dose cohorts consistent with previously reports. Due to the small number of pts studied, and moderate variability in PK reported for this drug, it is not possible to draw definitive conclusions regarding dose-proportionality.

Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.

P2, N=49, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting | Trial completion date: Apr 2028 --> Apr 2026 | Trial primary completion date: Jan 2025 --> Apr 2024

We previously reported that cisplatin-resistant (CR) tumors survive via oxidative metabolism and amino acid uptake, reducing immunosurveillance and viable cytotoxic T-cell populations...Inhibiting IDO1 (epacadostat; 200mg/kg/day; PO) reduced tumor growth (30%, n=7; p<0.05) in CR-bearing mice but induced the expression of tryptophan 2,3-dioxygenase-2 (TDO2) (alternate tryptophan degrading enzyme)...Dual IDO1/TDO2 inhibition potently reduced tumor growth and enhanced tumor immunosurveillance in CR NSCLC in vivo models. These results may inform: (i) how the KYN pathway can be exploited in treating CR NSCLC, (ii) the future application of immunotherapy, based on an improved understanding of how CRcells evade immune surveillance.; Public health; Endoscopy and interventional pulmonology; Cell and molecular biology; General respiratory patient care; Respiratory intensive care; Epidemiology; Surgery

Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.

P1/2, N=39, Recruiting, Washington University School of Medicine | Phase classification: P1 --> P1/2 | Trial completion date: Jun 2027 --> Aug 2030 | Trial primary completion date: Dec 2026 --> Jul 2027

Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

P3, N=129, Active, not recruiting, Incyte Corporation | Trial completion date: Feb 2023 --> Dec 2024

In our study, the therapeutic potentials of two different IDO inhibitors (Epacadostat [EPA] and 1-methyl-L-tryptophan [L-1MT]) in triple-negative breast cancer (TNBC) cells were assessed with and without tumor necrosis factor-α (TNF-α) stimulation...Our findings showed that the efficacy of IDO inhibitors was mediated by pro-inflammatory cytokine. However, different molecular signaling pathways are associated with pro-inflammatory cytokines production, and the expression of IDO1 and PD-L1 calls for further investigations.

Although epacadostat was effective in preclinical models and in early phase trials, it gave negative results in a metastatic melanoma randomized phase III study to test the benefit of adding epacadostat to the reference pembrolizumab therapy. Our data suggest that a possible explanation of epacadostat ineffectiveness may rely on the ability of this drug to enhance the other IDO1 immunoregulatory mechanism, involving intracellular signaling function. These findings open up a new perspective for IDO1 inhibitors developed as new anticancer drugs, which should be carefully evaluated for their ability to block not only the catalytic but also the signaling activity of IDO1.