《柳叶刀.肿瘤》:新型细胞周期检查点抑制剂靶向治疗复发性卵巢癌


卵巢癌是“最棘手”的妇科肿瘤

一旦发生复发或转移预后较差,细胞周期检查点抑制剂已在多种肿瘤中发挥了一定治疗效果,但其副作用及联合用药问题仍需进一步深入研究。近期发表在《柳叶刀.肿瘤》的最新文章探究了新型细胞周期检查点激酶抑制剂——prexasertib (LY2606368) 在高级别浆液性卵巢癌中的治疗前景。


研究背景:高级别浆液性卵巢癌的特点有TP53突变,DNA修复缺陷和基因组不稳定性。我们希望研究一种细胞周期检查点激酶1和2的抑制剂——prexasertib (LY2606368)是否在野生型BRCA卵巢癌中有效。


研究方法:在这项开放、单中心的II期临床研究中,我们纳入的是18岁以上,患有可测量、复发高级别浆液性或内膜样卵巢癌女性。所有病人均无遗传性乳腺癌或卵巢癌家族史,或无BRCA突变,有“实体肿瘤疗效评价标准”(RECIST,版本1.1)规定的可测量病灶,“东部肿瘤合作组织”规定的表现评分0-2分,以及血液、肾脏、肝脏和骨髓功能良好。患者接受prexasertib静脉给药105 mg/m2每14天一次,28天一周期,直到疾病进展,出现无法耐受的毒性或患者退出。主要结局为根据RECIST1.1,研究者所定义的抗肿瘤疗效,根据符合方案集进行评估(患者在初期和经过至少一次随访期间进行过CT检查)。


研究结果:在2015.1.20-2016.11.2期间,我们纳入28名女性,中位年龄为64岁(四分位数 58·0–69·5),她们之前接受过中位数为5次(IQR 2·5–5·0)的系统治疗。多数患者(22名[79%])患有顺铂耐药或难治性卵巢癌。所有女性患者至少接受过一次prexasertib治疗,但是28人中的4名患者(14%)无法用RECIST来评估疗效。24人中的8名患者(33%, 95% CI 16–55)符合方案集,有部分缓解。在意向性治疗人群中,28人中的8人(29%, 95% CI 13–49)疾病有部分缓解。最常见的(>10%受试者中)3或4级治疗紧急性副反应为中性粒细胞缺乏(28人中有26人出现[93%]),白细胞下降(23人[82%]),血小板减少(7人[25%])和贫血(3人[11%])。首次prexasertib 治疗后有22名患者(79%)发生4级粒缺,但均为短暂性(中位持续时间6天[IQR 4–8]),不需生长因子支持都可恢复。有2名患者(7%)出现治疗相关的3级发热性粒缺。一名患者在研究中因为疾病进展而死亡。


研究解读:Prexasertib在BRCA未突变的高级别浆液性卵巢癌中显现了一定的临床效果和可耐受性。基于这些结果,值得更进一步研发这一药物,尤其是对顺铂耐药或难治性卵巢癌患者。


摘要原文:


Background

High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease.


Methods

In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat.


Findings

Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression.


Interpretation

Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease.


Reference: Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study


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