Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months
Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months
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DOI：
10.1200/jco.2016.67.5942
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发表时间：
2016-12-20
影响因子：
45.3
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
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作者：
Leijen, Suzanne;van Geel, Robin M. J. M.;Schellens, Jan H. M.
目的 AZD1775 是一种一流的、有效的、选择性的 WEE1 抑制剂，已在临床前模型中证明对 p53 缺陷肿瘤具有化学增效作用。在一项 I 期研究中，AZD1775 与卡铂联合使用的最大耐受剂量证明了靶点参与。我们对一线铂类治疗难治或耐药（3 个月）的 p53 肿瘤抑制基因 (TP53) 突变卵巢癌患者进行了一项原理验证 II 期研究，以确定总体缓解率、无进展生存率和总体生存率、药代动力学以及皮肤活检中磷酸化细胞周期蛋白依赖性激酶 (CDK1) 的调节。 患者和方法患者接受卡铂治疗（曲线下面积，5） mg/mL$ min) 联合 AZD1775 225 mg 口服，每日两次，每 21 天周期 2.5 天，直至疾病进展。结果 AZD1775 加卡铂表现出可控制的毒性；疲劳（87%）、恶心（78%）、血小板减少（70%）、腹泻（70%）和呕吐（48%）是最常见的不良事件。最常见的 3 级或 4 级不良事件是血小板减少症 (48%) 和中性粒细胞减少症 (37%)。在 24 名入组患者中，21 名患者的疗效终点可进行评估。总体缓解率为 43%（95% CI，22% 至 66%），其中一名患者 (5%) 具有长期完全缓解。中位无进展生存时间和总生存时间分别为 5.3 个月（95% CI，2.3 至 9.0 个月）和 12.6 个月（95% CI，4.9 至 19.7），其中两名患者在数据截止时持续缓解超过 31 个月和 42 个月。结论据我们所知，这是第一份提供临床证据证明 AZD1775 增强卡铂疗效的报告TP53 突变肿瘤。在一线治疗难治或耐药（< 3 个月）的 TP53 突变卵巢癌患者中观察到的令人鼓舞的抗肿瘤活性值得进一步开发。 (C) 2016 年美国临床肿瘤学会
PurposeAZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proofof- principle phase II study in patients with p53 tumor suppressor gene (TP53)-mutated ovarian cancer refractory or resistant (, 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies.Patients and MethodsPatients were treated with carboplatin (area under the curve, 5 mg/mL$ min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression.ResultsAZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff.ConclusionTo our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development. (C) 2016 by American Society of Clinical Oncology