University College London (UCL) Cancer Institute, UCL, London, UK.
Clinical Oncological Dispensary #1, Healthcare Department of Krasnodar Region, Krasnodar, Russia.
Gynecol Oncol. 2017 Sep;146(3):484-490. doi: 10.1016/j.ygyno.2017.07.005. Epub 2017 Jul 8.
Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer.
In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability.
The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples.
This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.
吲哚胺 2,3-双加氧酶-1（IDO1）是卵巢癌免疫耐受的关键调节因子。本研究旨在探讨 IDO1 酶抑制剂依帕司他与他莫昔芬在一线化疗后完全缓解、但随后出现生物化学复发（CA-125 升高）的晚期上皮性卵巢癌、原发性腹膜癌或输卵管癌患者中的疗效和安全性。
这是一项开放标签、二期研究（NCT01685255），患者按 1:1 随机分配至依帕司他 600mg 或他莫昔芬 20mg 每日 2 次，连续 28 天为一个周期，并根据从一线化疗结束到首次 CA-125 升高的时间（3 至＜12 个月或≥12 个月）进行分层。主要终点为研究者评估的无进展生存期（PFS；RECIST v1.1）。次要终点包括 CA-125 反应（妇科肿瘤协作组标准）、总生存期、安全性和耐受性。
研究主要因入组缓慢和缺乏优势证据而提前终止。依帕司他组（n=22）的中位 PFS 为 3.75 个月，他莫昔芬组（n=20）为 5.56 个月（HR，1.34 [95%CI，0.58-3.14]；P=0.54）。可评估患者中，依帕司他组有 1 例（5.0%）和他莫昔芬组有 3 例（15.8%）确认 CA-125 有缓解。最常见的治疗相关不良事件为疲劳（依帕司他组 36.4%，他莫昔芬组 40.0%）。仅在依帕司他组观察到免疫相关不良事件，主要为皮疹（18.2%）和瘙痒（9.1%）。依帕司他的药代动力学/药效学与已知的作用机制一致。94%的存档肿瘤样本中观察到 IDO1 表达。
这是首个关于免疫治疗在生物化学复发卵巢癌中的评估报告，也是首个关于 IDO1 抑制剂单药治疗卵巢癌的报告，结果显示依帕司他与他莫昔芬在疗效方面无显著差异。依帕司他总体耐受性良好。
