Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.
Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.
复制标题
DOI：
10.1016/s1470-2045(20)30180-7
复制
发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Matulonis UA
中科院分区：
文献类型：
--
作者：
Konstantinopoulos PA;Cheng SC;Wahner Hendrickson AE;Penson RT;Schumer ST;Doyle LA;Lee EK;Kohn EC;Duska LR;Crispens MA;Olawaiye AB;Winer IS;Barroilhet LM;Fu S;McHale MT;Schilder RJ;Färkkilä A;Chowdhury D;Curtis J;Quinn RS;Bowes B;D'Andrea AD;Shapiro GI;Matulonis UA
高级别浆液性卵巢癌表现出增加的复制应激，由于G1/S检查点的几乎普遍丢失（通过有害的TP 53突变）、过早进入S期（由于CCNE 1扩增、RB 1丢失或CDKN 2A mRNA下调）、同源重组修复基因的改变和致癌驱动因子的表达（通过MYC扩增和其他机制），使细胞容易受到ATR抑制。我们假设选择性ATR抑制剂贝佐塞替和吉西他滨联合治疗高级别浆液性卵巢癌的毒性可接受，疗效上级吉西他滨单药治疗。在这项多中心、开放标签、随机、2期研究中，美国实验性治疗药物临床试验网络的11个不同中心招募了女性患者。（年龄≥18岁）复发性、铂类耐药的高级别浆液性卵巢癌（组织学测定）和东部肿瘤协作组体能状态为0或1，在铂类敏感环境中既往接受过无限线细胞毒性治疗，但在铂类耐药环境中接受过不超过一线细胞毒性治疗的患者。合格患者被随机分配（1：1）接受吉西他滨（1000 mg/m2）静脉给药（第1天和第8天），或吉西他滨联合贝佐塞替（210 mg/m2）静脉给药（第2天和第9天），21天为一个周期，直至疾病进展或出现不可耐受的毒性。使用Theradex交互式网络应答系统集中进行随机化，按无铂间隔分层，排列区组大小为6。中心随机化后，患者和研究者不对治疗分配设盲。主要终点是研究者评估的无进展生存期，分析包括至少接受一剂研究药物的所有患者。该研究注册于ClinicalTrials.gov，NCT 02595892，并处于活动状态，但已关闭入组。在2017年2月14日至2018年9月7日期间，对88例患者进行了合格性评估，其中70例患者被随机分配接受吉西他滨单药治疗（36例患者）或吉西他滨+贝佐塞替治疗（34例患者）。截至数据截止日期（2020年2月21日），吉西他滨联合贝佐塞替组的中位随访时间为53·2周（25·6-81·8），吉西他滨单药组为43·0周（IQR 23·2-69·1）。吉西他滨联合贝佐舍替的中位无进展生存期为22.9周（17.9 - 72.0），吉西他滨单药治疗的中位无进展生存期为14.7周（90% CI 9.7 - 36.7）（风险比0.57，90% CI 0.33-0.98;单侧对数秩检验p= 0.044）。最常见的治疗相关3级或4级不良事件为中性粒细胞计数降低（吉西他滨单药组36例患者中的14例[39%] vs吉西他滨+贝佐舍替组34例患者中的16例[47%]）和血小板计数降低（2例[6%] vs 8例[24%]）。在吉西他滨单药组的10例（28%）患者和吉西他滨+贝佐舍替组的9例（26%）患者中观察到严重不良事件。吉西他滨单药治疗组中有1例治疗相关死亡是由于败血症，吉西他滨+贝佐舍替组中有1例治疗相关死亡是由于肺炎。据我们所知，这是ATR抑制剂在任何肿瘤类型中的首次随机研究。这项研究表明，在吉西他滨中添加贝佐塞替对铂耐药的高级别浆液性卵巢癌有好处。这种组合需要在这种情况下进行进一步的研究。美国国家癌症研究所。
High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment. Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6–81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2–69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9–72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7–36·7) for gemcitabine alone (hazard ratio 0.57, 90% CI 0.33–0.98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. US National Cancer Institute.