Discussion
tumor, tumors, melanoma
TUMOR, TUMORS, SOLID TUMORS, MELANOMA
ECHO-206 represents the largest prospective study of combination treatment with an epigenetic modulator (azacitidine) and immunotherapy (epacadostat plus pembrolizumab) performed to date. Although this study established that azacitidine 100 mg could be safely combined with epacadostat and pembrolizumab, this regimen (with all agents administered concurrently or with a lead-in) was not associated with substantial clinical response in patients with immunotherapy-resistant solid tumors (predominately MSS CRC) or solid tumors that progressed following immunotherapy (predominately melanoma). Whether use of azacitidine could enhance immunotherapy response in the treatment naïve setting is unclear. Our findings contrast with preliminary results from the Phase I/II ENCORE-601 study, which evaluated combination treatment with the DNMT inhibitor entinostat and pembrolizumab in patients with anti-PD-1–refractory advanced tumors [The strategy of targeting the Trp–Kyn–AhR pathway through IDO1 inhibition experienced a setback following the negative results of the Phase III KEYNOTE-252/ECHO-301 study [Although preclinical findings strongly suggest an ability of epigenetic modulators to facilitate an influx of T cells into the tumor microenvironment [With the doses of pembrolizumab and azacitidine used in this study, we believe pharmacodynamic changes and/or any clinical benefit with combination treatment would have been observed. However, dosing of epacadostat may have been insufficient. A longitudinal analysis of plasma samples acquired from participants across multiple clinical studies revealed that epacadostat doses <600 mg BID were not sufficient to reduce plasma kynurenine levels when combined with PD-1 inhibition [It is apparent that many questions remain regarding the potential of epigenetic modifiers in enhancing the clinical activity of immunotherapy. Other epigenetic modifiers of clinical interest include agents targeting protein arginine methyltransferase 5, SET domain bifurcated, lysine demethylase 1, and cyclin-dependent kinase 9. These agents have all been demonstrated in the preclinical setting to induce viral mimicry responses, regulate type I and II IFN responses, and/or enhance the antitumor activity of PD-(L)1 inhibitors [In summary, we performed the largest prospective study to date combining epigenetic modulation (azacitidine) with IDO1 inhibition (epacadostat) and immune checkpoint blockade (pembrolizumab). We demonstrated that both epigenetic lead-in and concurrent therapy were moderately well-tolerated. However, overall efficacy was limited in our cohort of patients, the majority of whom had either prior experience with immunotherapy or had immunotherapy-refractory tumors. Although the DNMT inhibitor azacitidine suppressed influx of intratumoral regulatory T cells, no increase in the numbers of effector T cells was observed, suggesting that the ability of azacitidine to influence intratumoral CD8