Vita-Salute San Raffaele University Milan, Milan, Italy.
Department of Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
BMC Cancer. 2024 Jul 25;23(Suppl 1):1252. doi: 10.1186/s12885-023-10727-3.
Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC.
ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1).
A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%).
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.
ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.
吲哚胺 2,3-双加氧酶 1（IDO1）是一种免疫抑制酶，与尿路上皮癌（UC）患者的疾病特异性生存时间缩短相关。IDO1 可能会抵消免疫检查点抑制剂的抗肿瘤作用。Epacadostat 是一种强效且高度选择性的 IDO1 抑制剂。在 I/II 期 ECHO-202/KEYNOTE-037 研究中，Epacadostat 加 pembrolizumab 在一组晚期 UC 患者中产生了初步的客观缓解率（ORR）为 35%。
ECHO-307/KEYNOTE-672 是一项双盲、随机、III 期研究。合格的成年人患有经确认的局部晚期/不可切除或转移性尿路 UC，不符合顺铂为基础的化疗条件。参与者被随机分配（1:1）接受 Epacadostat（100mg 每日两次）加 pembrolizumab（200mg 每 3 周）或安慰剂加 pembrolizumab 治疗，最多 35 次 pembrolizumab 输注。主要终点是根据实体瘤反应评估标准（版本 1.1）评估的研究者评估的 ORR。
共有 93 名患者被随机分配（epacadostat 加 pembrolizumab，n=44；安慰剂加 pembrolizumab，n=49）。由于来自 III 期 ECHO-301/KEYNOTE-252 研究的新数据，入组提前停止。在两个臂中，中位随访时间均为 64 天。根据截止日期的所有可用数据，ORR（未确认）在 epacadostat 加 pembrolizumab 组为 31.8%（95%CI，22.46-55.24%），在安慰剂加 pembrolizumab 组为 24.5%（95%CI，15.33-43.67%）。在安慰剂加 pembrolizumab 臂中，循环犬尿氨酸水平从 C1D1 到 C2D1 数值增加，而在 epacadostat 加 pembrolizumab 臂中则减少。epacadostat 加 pembrolizumab 联合治疗耐受性良好，安全性与安慰剂相似。由于治疗相关不良事件而停药的情况在 epacadostat 组更为频繁（11.6% vs. 4.1%）。
在不符合顺铂治疗条件的未经治疗的局部晚期/不可切除或转移性 UC 患者中，epacadostat 加 pembrolizumab 治疗的 ORR 和安全性与安慰剂加 pembrolizumab 相似。在每日两次 100mg 的剂量下，当与 pembrolizumab 联合使用时，epacadostat 似乎并未完全使循环犬尿氨酸水平正常化。可能需要进行更大规模的研究，随访时间更长，可能需要测试更高剂量的 epacadostat，可能在不同的治疗环境中进行。
ClinicalTrials.gov 标识符：NCT03361865，于 2017 年 12 月 5 日回顾性注册。
