Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96): a multicentre, randomised, double-blind, phase 3 study.

We investigated whether adding pembrolizumab to weekly paclitaxel, with or without bevacizumab, improves progression-free survivaland overall survivalcompared with weekly paclitaxel, with or without bevacizumab, in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens.

我们研究了在铂类耐药的复发性卵巢癌患者中，与每周使用紫杉醇（无论是否联合贝伐单抗）相比，添加 pembrolizumab 是否能改善无进展生存期和总生存期，这些患者之前已经接受了1至2个全身治疗方案。

Methods

ENGOT-ov65/KEYNOTE-B96 is a randomised, double-blind, phase 3 study conducted at 187 gynaecologic oncology centres in 25 countries in the Americas, Asia, Europe, and Oceania.

ENGOT-ov65/KEYNOTE-B96是在美洲、亚洲、欧洲和大洋洲25个国家的187个妇科肿瘤中心进行的一项随机、双盲、III期研究。

Adults (≥18 years) with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum regimen, were eligible.

年龄≥18岁的成人患者，经组织学证实为上皮性卵巢癌、输卵管癌或原发性腹膜癌，且接受过一至两次全身治疗（包括至少一种铂类方案），并在最后一次铂类方案治疗后6个月或更短时间内疾病进展，符合入选条件。

Participants were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo (saline solution) every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator.

参与者被随机分配为1:1，接受静脉注射帕博利珠单抗400 mg，每6周一次，最多18个周期，加上开放标签的静脉注射紫杉醇80 mg/m2，每个21天周期的第1天、第8天和第15天；或者接受静脉注射安慰剂（生理盐水溶液），每6周一次，最多18个周期，加上开放标签的静脉注射紫杉醇80 mg/m2，每个21天周期的第1天、第8天和第15天；根据研究者判断，允许每2周静脉注射贝伐珠单抗10 mg/kg。

Randomisation was stratified by planned bevacizumab use, region, and PD-L1 combined positive score (CPS).

随机分组按计划使用贝伐珠单抗、地区和PD-L1综合阳性评分（CPS）进行分层。

The primary endpoint was investigator-assessed progression-free survivalper RECIST version 1.1; the key secondary endpoint was overall survival. Results from two interim analyses and the final analysis are included in this Article.

主要终点是根据RECIST版本1.1评估的无进展生存期，主要次要终点是总生存期。本文包括了两次中期分析和最终分析的结果。

This study is registered with ClinicalTrials.gov, NCT05116189, and is now completed.

该研究已在ClinicalTrials.gov上注册，编号为NCT05116189，并已结束。

Results

Between Dec 13, 2021, and July 3, 2023, 643 female participants were randomly assigned; 322 to pembrolizumab plus paclitaxel and 321 to placebo plus paclitaxel.

2021年12月13日至2023年7月3日期间，共有643名女性参与者被随机分配；其中322名接受帕博利珠单抗联合紫杉醇治疗，另外321名接受安慰剂联合紫杉醇治疗。

At the first interim analysis, pembrolizumab plus paclitaxel significantly improved progression-free survivalversus placebo plus paclitaxel in both the PD-L1 CPS 1 or higher (median 8·3 months vs 7·2 months; hazard ratio[HR] 0·72; 95% CI 0·58-0·89; p=0·0014 α=0·012]) and overall populations (median 8·3 months vs 6·4 months; HR 0·70, 95% CI 0·58-0·84; p<0·0001, [α=0·0023]), meeting the prespecified criteria for confirmatory efficacy.

在首次中期分析中，帕博利珠单抗联合紫杉醇治疗显著改善了PD-L1 CPS 1或更高（中位无进展生存期8.3个月 vs 7.2个月；风险比[HR] 0.72；95%置信区间0.58-0.89；p=0.0014 α=0.012）以及整体人群（中位无进展生存期8.3个月 vs 6.4个月；HR 0.70，95%置信区间0.58-0.84；p<0.0001，[α=0.0023]）的无进展生存期，达到了预先设定的确证性疗效标准。

At the second interim analysis, overall survivalwas significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76, 95% CI 0·61-0·94; p=0·0053, [α=0·0083]).

在第二次中期分析中，PD-L1 CPS 1或更高的人群总生存期显著改善（中位数18.2个月对比14.0个月；风险比0.76，95%置信区间0.61-0.94；p=0.0053，[α=0.0083]）。

At the final analysis, overall survivalwas significantly improved in the overall population (median 17·7 months vs 14·0 months; HR 0·82, 95% CI 0·69-0·97; p=0·011 [α=0·024]).

在最终分析中，整体人群的总生存期显著改善（中位数17.7个月对比14.0个月；风险比0.82，95%置信区间0.69-0.97；p=0.011 [α=0.024]）。

Grade 3 or worse treatment-related adverse events occurred in 217 (68%) of 320 participants in the pembrolizumab plus paclitaxel group versus 176 (55%) of 318 participants in the placebo plus paclitaxel group.

在320名接受派姆单抗联合紫杉醇治疗的参与者中，有217人（68%）出现了3级或更严重的治疗相关不良事件，而在318名接受安慰剂联合紫杉醇治疗的参与者中，有176人（55%）出现了3级或更严重的治疗相关不良事件。

The most common treatment-related adverse events (any grade) included anaemia, peripheral neuropathy, alopecia, fatigue, and nausea.

最常见的治疗相关不良事件（任何级别）包括贫血、周围神经病变、脱发、疲劳和恶心。

Treatment-related adverse events resulted in death in four participants (1%) in the pembrolizumab plus paclitaxel group (colitis, interstitial lung disease, acute myeloid leukaemia, and intestinal perforation) and in five participants (2%) in the placebo plus paclitaxel group (cardiac failure, intestinal perforation [in two participants], and large-intestine perforation [in two participants]).

治疗相关不良事件导致 pembrolizumab 加 paclitaxel 组的四名参与者（1%）死亡（结肠炎、间质性肺病、急性髓细胞性白血病和肠穿孔），以及安慰剂加 paclitaxel 组的五名参与者（2%）死亡（心脏衰竭、肠穿孔[两名参与者]和大肠穿孔[两名参与者]）。

interpretation

Pembrolizumab plus weekly paclitaxel, with or without bevacizumab, significantly improved progression-free survivaland overall survivalin participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens, supporting this regimen as a new treatment option for this population.

Pembrolizumab 加上每周一次的 paclitaxel，无论是否加用 bevacizumab，显著改善了接受过一到两个全身治疗方案的铂类耐药复发性卵巢癌患者的无进展生存期和总生存期，支持将此方案作为这一人群的新治疗选择。

funding

Funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

本研究由美国新泽西州拉威默克夏普与多姆公司资助，该公司是默克公司的子公司。