Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
National Cancer Hospital East, Kashiwa, Japan.
Lancet. 2023 Dec 9;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0. Epub 2023 Oct 20.
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 ClinicalTrials.gov (NCT03615326) 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 vs 145 [42%] in the placebo group), nausea (154 [44%] vs 152 [44%]), and anaemia (109 [31%] vs 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.
在 HER2 阳性胃食管交界处腺癌患者中，联合 PD-1 和 HER2 阻断剂与化疗相比，在无进展生存期和总生存期方面的疗效证据有限。随机、III 期 KEYNOTE-811 研究的第一次中期分析显示，与安慰剂相比，pembrolizumab 联合曲妥珠单抗加氟嘧啶和铂类化疗时，客观缓解率更高。在此，我们报告了 KEYNOTE-811 的协议规定的后续中期分析结果。
这项随机、III 期 KEYNOTE-811 试验涉及全球 20 个国家的 168 个医疗中心。年龄在 18 岁或以上的局部晚期或转移性 HER2 阳性胃食管交界处腺癌患者，未经一线治疗，按 1:1 比例通过集成的交互式语音响应和网络响应系统随机分配（1:1），静脉注射 pembrolizumab 200mg 或安慰剂，两者均与标准化疗（氟嘧啶和铂类药物治疗）联合，每 3 周给药，最多 35 个周期，或直至疾病进展、不可接受的毒性作用、研究者或参与者发起的停药。随机分组采用大小为 4 的分组块，并按区域、PD-L1 状态和化疗分层。主要终点是无进展生存期和总生存期，采用意向治疗进行分析。根据接受的治疗，对至少接受一剂研究治疗的所有随机分配患者进行安全性评估。KEYNOTE-811 在 ClinicalTrials.gov（NCT03615326）上注册，目前处于活跃状态但未招募。
在 2018 年 10 月 5 日至 2021 年 8 月 6 日期间，698 名患者被分配到 pembrolizumab 组（n=350）或安慰剂组（n=348）。564 名（81%）为男性，134 名（19%）为女性。在第三次中期分析时，pembrolizumab 组 350 名患者中有 286 名（82%）和安慰剂组 346 名患者中有 304 名（88%）接受了治疗后停止治疗，主要原因是疾病进展。在第二次中期分析时（pembrolizumab 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]），pembrolizumab 组无进展生存期的中位数为 10.0 个月（95%CI 8.6-11.7），安慰剂组为 8.1 个月（7.0-8.5）（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）vs 16.9 个月（15.0-19.8；HR 0.87 [0.72-1.06]；p=0.15）。在第三次中期分析时（pembrolizumab 组中位随访 38.4 个月[IQR 29.5-44.4]，安慰剂组中位随访 38.6 个月[30.2-44.4]），无进展生存期的中位数为 10.0 个月（8.6-12.2），安慰剂组为 8.1 个月（7.1-8.6）（HR 0.73 [0.61-0.87]），总生存期的中位数为 20.0 个月（17.8-22.1），安慰剂组为 16.8 个月（15.0-18.7）（HR 0.84 [0.70-1.01]），但未达到预设的显著标准，将继续进行最终分析。pembrolizumab 组中有 204 名（58%）患者和安慰剂组中有 176 名（51%）患者发生了 3 级或更严重的治疗相关不良事件。pembrolizumab 组中有 4 名（1%）患者和安慰剂组中有 3 名（1%）患者发生了与治疗相关的导致死亡的不良事件。任何级别最常见的治疗相关不良事件是腹泻（pembrolizumab 组 165 例[47%]，安慰剂组 145 例[42%]）、恶心（pembrolizumab 组 154 例[44%]，安慰剂组 152 例[44%]）和贫血（pembrolizumab 组 109 例[31%]，安慰剂组 113 例[33%]）。
与安慰剂相比，pembrolizumab 联合曲妥珠单抗和一线化疗治疗转移性 HER2 阳性胃食管交界处腺癌时，特别是在 PD-L1 联合阳性评分≥1 的肿瘤患者中，显著改善了无进展生存期。总生存期的随访仍在进行中，将在最终分析时报告。
默克公司。
