Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811. The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with () and is active but not recruiting. Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4–34·3] in the pembrolizumab group and 28·5 months [20·1–34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6–11·7) in the pembrolizumab group versus 8·1 months (7·0–8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60–0·87; p=0·0002). Median overall survival was 20·0 months (17·8–23·2) versus 16·9 months (15·0–19·8; HR 0·87 [0·72–1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5–44·4] in the pembrolizumab group and 38·6 months [30·2–44·4] in the placebo group), median progression-free survival was 10·0 months (8·6–12·2) versus 8·1 months (7·1–8·6; HR 0·73 [0·61–0·87]), and median overall survival was 20·0 months (17·8–22·1) versus 16·8 months (15·0–18·7; HR 0·84 [0·70–1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 (58%) of 350 patients in the pembrolizumab group versus 176 (51%) of 346 patients in the placebo group. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group and three (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhoea (165 [47%] in the pembrolizumab group 145 [42%] in the placebo group), nausea (154 [44%] 152 [44%]), and anaemia (109 [31%] 113 [33%]). Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis. Merck Sharp & Dohme.

中文翻译：

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帕博利珠单抗联合曲妥珠单抗和化疗治疗 HER2 阳性胃或胃食管交界腺癌：3 期 KEYNOTE-811 随机安慰剂对照试验的中期分析

关于 PD-1 和 HER2 阻断联合化疗对 HER2 阳性胃食管癌无进展生存期和总生存期的疗效的证据很少。随机 3 期 KEYNOTE-811 研究的首次中期分析显示，当加入曲妥珠单抗加氟嘧啶和铂类化疗时，与安慰剂相比，派姆单抗具有更好的客观反应。在这里，我们报告了 KEYNOTE-811 协议指定的后续中期​​分析的结果。KEYNOTE-811 随机 3 期试验涉及全球 20 个国家的 168 个医疗中心。年龄 18 岁或以上、患有局部晚期或转移性 HER2 阳性胃食管交界处腺癌且既往未接受过一线治疗的患者，通过集成交互式语音应答和网络​​应答系统被随机分配 (1:1) 接受静脉注射派姆单抗200 mg 或安慰剂，均与标准化疗（氟嘧啶和铂类疗法）联合曲妥珠单抗每 3 周一次，持续最多 35 个周期，或直至疾病进展、不可接受的毒性作用或研究者或参与者发起的退出。随机分组使用 4 组大小，并按区域、PD-L1 状态和化疗进行分层。双重主要终点是无进展生存期和总生存期，按意向治疗进行分析。根据所接受的治疗，对所有接受至少一剂研究治疗的随机分配的患者进行安全性评估。KEYNOTE-811 已注册（），处于活跃状态，但尚未招募。2018年10月5日至2021年8月6日期间，698名患者被分配至派姆单抗组（n=350）或安慰剂组（n=348）。564 名（81%）为男性，134 名（19%）为女性。在第三次中期分析中，接受治疗的派姆单抗组 350 名患者中有 286 名患者（82%）和安慰剂组 346 名患者中有 304 名患者（88%）停止了治疗，主要是由于疾病进展。在第二次中期分析时（派姆单抗组中位随访 28·3 个月 [IQR 19·4–34·3]，安慰剂组中位随访 28·5 个月 [20·1–34·3]），中位进展派姆单抗组的无生存期为 10·0 个月 (95% CI 8·6–11·7)，而安慰剂组的无生存期为 8·1 个月 (7·0–8·5)（风险比 [HR] 0· 72，95% CI 0·60–0·87；p=0·0002）。中位总生存期为 20·0 个月 (17·8–23·2) 对比 16·9 个月 (15·0–19·8；HR 0·87 [0·72–1·06]；p=0·084 ）。在第三次中期分析时（派姆单抗组的中位随访时间为 38·4 个月 [IQR 29·5–44·4]，安慰剂组的中位随访时间为 38·6 个月 [30·2–44·4]），中位进展无生存期为 10·0 个月 (8·6–12·2) 对比 8·1 个月 (7·1–8·6；HR 0·73 [0·61–0·87])，中位总生存期为 20·0 个月 (17·8–22·1) 与 16·8 个月 (15·0–18·7；HR 0·84 [0·70–1·01])，但不符合预先指定的标准意义重大，将继续进行最后的分析。派姆单抗组 350 名患者中有 204 名患者（58%）发生了 3 级或更严重的治疗相关不良事件，而安慰剂组 346 名患者中有 176 名患者（51%）发生了 3 级或更严重的治疗相关不良事件。派姆单抗组有 4 名患者 (1%) 发生了导致死亡的治疗相关不良事件，安慰剂组有 3 名患者 (1%) 发生了导致死亡的治疗相关不良事件。最常见的任何级别的治疗相关不良事件是腹泻（派姆单抗组中有 165 例 [47%]，安慰剂组有 145 例 [42%]）、恶心（154 例 [44%] 152 例 [44%]）和贫血（109 [31%] 113 [33%]）。与安慰剂相比，派姆单抗与一线曲妥珠单抗和化疗联合治疗转移性 HER2 阳性胃食管癌时，可显着改善无进展生存期，特别是对于 PD-L1 综合阳性评分为 1 或更高的肿瘤患者。总体生存随访正在进行中，并将在最终分析时报告。默克夏普和多姆。