IDO (indoleamine 2,3-dioxygenase) is an intracellular enzyme that regulates immune response by degrading tryptophan to kynurenine which results in a suppressive phenotype. IDO is over-expressed in multiple tumors including melanoma, and its higher expression is associate with worse prognosis. Multiple IDO inhibitors have been tested in clinical trials setting with different malignancies, majority of them are direct enzymatic inhibitors (epacadostat, linrodostat), as opposed to indoximod (a tryptophan memetic), Acts directly on immune cells to reverse IDO pathway-mediated suppression. Preclinical data suggested the synergy between IDO and PD-1 inhibition along with multiple early phase clinical trials. In a phase 2 clinical trial combining indoximod and pembrolizumab in treatment naïve metastatic melanoma patients, the overall response rate (ORR) in 89 patients was 51% with confirmed complete response of 70% and median progression free survival of 12.4 months. The combination was well tolerated. With the negative phase 3 trial combining epacadostat and pembrolizumab in metastatic melanoma, the enthusiasm about IDO pathway is dampened, the reason for failure of this clinical trial is unknown. Questions have been raised about the reduced dose of epacadostat used (100 mg two times a day). Multiple ongoing clinical trials currently evaluating different IDO inhibitors in different types of malignancies. Further evaluation is melanoma is still warranted.
1. Learn about IDO pathway
2. IDO rule in cancer