UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Br J Cancer. 2023 Jun;128(12):2227-2235. doi: 10.1038/s41416-023-02267-1. Epub 2023 Apr 22.
Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors.
ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or pharmacologically active dose (PAD; Phase I), and investigator-assessed objective response rate (ORR; Phase II).
In Phase I, no dose-limiting toxicities were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, with four partial responses. The most common treatment-related adverse events (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients experienced ≥1 fatal AE, one of which (asthenia) was treatment-related.
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.
吲哚胺 2,3-双加氧酶 1（IDO1）是一种干扰素诱导的酶，有助于肿瘤免疫耐受。免疫检查点抑制可能会增加干扰素水平；IDO1 抑制与免疫检查点阻断相结合代表了一种有吸引力的策略。表观遗传药物会引发干扰素反应，并且可以作为免疫治疗的启动方法。我们评估了表观遗传治疗联合 IDO1 抑制和免疫检查点阻断是否能为晚期实体瘤患者带来临床获益。
ECHO-206 是一项 I/II 期研究，其中接受过治疗的晚期实体瘤患者（N=70）接受阿扎胞苷加免疫治疗双联（epacadostat[IDO1 抑制剂]和 pembrolizumab）。还评估了治疗的测序。主要终点是安全性/耐受性（I 期）、最大耐受剂量（MTD）或药效学剂量（PAD；I 期）和研究者评估的客观缓解率（ORR；II 期）。
在 I 期，未报告剂量限制毒性，未达到 MTD；未确定 PAD。ORR 为 5.7%，有 4 例部分缓解。最常见的治疗相关不良事件（AE）是疲劳（42.9%）和恶心（42.9%）。12 名（17.1%）患者发生≥1 例致命 AE，其中 1 例（乏力）与治疗相关。
尽管阿扎胞苷-epacadostat-pembrolizumab 方案耐受性良好，但在先前接受过免疫治疗的晚期实体瘤患者中，与实质性临床反应无关。
