Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.
Highlights
With increasing recognition of evading immunological destruction as a hallmark of cancer acquired during its development[1], immunotherapy has emerged as a novel and important pillar of cancer treatment in addition to surgery, radiation, chemotherapy, and targeted therapy
The results showed that the safety profile of epacadostat was manageable and it can be generally well tolerated at doses of up to 700 mg twice daily (BID)
TRP deprivation is significantly correlated with clinical outcomes like the quality of life in colorectal cancer (CRC), survival in malignant melanoma and advanced disease stage in lung cancer[39–41] while the KYN generation has a prognostic significance in adult T-cell leukemia/lymphoma (ATL)[42]
Summary
With increasing recognition of evading immunological destruction as a hallmark of cancer acquired during its development[1], immunotherapy has emerged as a novel and important pillar of cancer treatment in addition to surgery, radiation, chemotherapy, and targeted therapy. The phase II trial of epacadostat in combination with nivolumab, i.e. ECHO-204 (NCT02327078) having similar study design and patient population demonstrated consistently promising anti-tumor activity with objective response at 62 % and tolerable safety profile in 50 patients with advanced malignant melanoma[77]. Regardless of the lack of evidence from at least one randomized, active controlled (anti-PD-1 antibody monotherapy) phase II trial as a validation step, the phase III trial ECHO-301/KEYNOTE-252 was initiated to further clarify the clinical benefit of epacadostat plus pembrolizumab compared to pembrolizumab alone in patients with advanced malignant melanoma previously untreated with a ICPI using PFS as primary endpoint In this trial, the testing of IDO1 expression status by use of in situ hybridization RNA scope technology was retrospectively completed after patients were enrolled, but was not taken into account in the treatment assignment or primary analysis of the endpoints. Near maximal changes observed at doses of ≥ 100 mg BID with > 80–90 % IDO1
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