Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study
Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study
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DOI：
10.1200/jco.2016.72.1340
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发表时间：
2017-07-01
影响因子：
45.3
通讯作者：
Kohn, Elise C.
中科院分区：
文献类型：
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作者：
Lee, Jung-Min;Cimino-Mathews, Ashley;Kohn, Elise C.
研究目的：研究表明，通过抑制聚ADP-核糖聚合酶而导致的DNA损伤和/或通过抑制血管内皮生长因子受体而导致的血管内皮生长因子信号转导的减少可能会补充免疫检查点阻断的抗肿瘤活性。我们假设程序性死亡配体1（PD-L1）抑制剂，durvalumab，olaparib，或cediranib组合是可耐受的，并在复发性women's cancer.Patients和MethodsThis阶段I研究平行3 + 3剂量递增测试durvalumab双联体。Durvalumab以10 mg/kg每2周一次或1，500 mg每4周一次与奥拉帕尼片剂每日两次或西地尼布以两种时间表给药。主要终点是推荐的II期剂量（RP 2D）。反应率和药代动力学分析是次要终点。ResultsBetween 2015年6月和2016年5月，26名妇女参加。RP 2D为durvalumab 1，500 mg，每4周一次，奥拉帕尼300 mg，每日两次，或西地尼布20 mg，给药5天/停药2天。durvalumab+奥拉帕尼未记录到剂量限制性毒性。检查西地尼布间歇给药方案（n = 6），因为每日给药方案（n = 8）出现复发性2级和非剂量限制性毒性3级和4级不良事件（AE）。治疗后出现的AE包括高血压（2/8）、腹泻（2/8）、肺栓塞（2/8）、肺动脉高压（1/8）和淋巴细胞减少症（1/8）。Durvalumab+间歇性西地尼布3级和4级AE为高血压（1/6）和疲乏（1/6）。durvalumab暴露增加了西地尼布的曲线下面积和每日最大血药浓度，但不是间歇性的。在接受durvalumab + olaparib治疗的患者中，观察到2例部分缓解（>= 15个月和>= 11个月）和8例稳定疾病>= 4个月（中位数，8个月[4至14.5个月]），疾病控制率为83%。在接受durvalumab联合西地尼布治疗的12例可评价患者中，观察到6例部分缓解（>= 5至>= 8个月）和3例疾病稳定>= 4个月（4至>= 8个月），缓解率为50%，疾病控制率为75%。对治疗的反应是独立的PD-L1 expression.ConclusionTo我们的知识，这是第一次报道的抗PD-L1加奥拉帕尼或西地尼布联合治疗。durvalumab+奥拉帕尼和durvalumab+间歇性西地尼布的RP 2D是可耐受的和活性的。生物标志物评价的II期研究正在进行中。(C)2017年美国临床肿瘤学会
PurposeData suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers.Patients and MethodsThis phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points.ResultsBetween June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism(two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (>= 15 months and >= 11 months) and eight stable diseases >= 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (>= 5 to >= 8 months) and three stable diseases >= 4months (4 to >= 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression.ConclusionTo our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing. (C) 2017 by American Society of Clinical Oncology