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| 新辅助/辅助帕博利珠单抗联合化疗在局部进展期胃或胃食管结合部腺癌中的疗效及安全性： KEYNOTE-585研究的期中分析 |
| Efficacy and safety of neoadjuvant/adjuvant pembrolizumab plus chemotherapy in locally-advanced gastric and gastroesophageal junction cancer: an interim analysis of the KEYNOTE-585 study |
| 投稿时间：2024-03-27 修订日期：2024-03-29 |
| DOI： |
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| 中文关键词: 胃或胃食管结合部腺癌 帕博利珠单抗 期中分析 |
| 英文关键词:gastric and gastroesophageal junction adenocarcinoma, pembrolizumab, interim analysis |
| 基金项目: |
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| 摘要点击次数: 54 |
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| 中文摘要: |
| 研究背景：对于局部进展期可切除的胃或胃食管结合部腺癌，联合新辅助/辅助化疗和免疫检查点抑制剂的获益尚不清楚。本次KEYNOTE-585研究的期中分析结果报告了新辅助/辅助帕博利珠单抗联合化疗在局部进展期可切除胃或胃食管结合部腺癌患者中的疗效及安全性。
研究方法：研究者在24个国家的143个中心进行了一项随机双盲、安慰剂对照III期临床研究。该研究招募了年龄18岁以上、既往未经治疗且可切除的局部进展期胃或胃食管结合部腺癌患者(≥T3或N+)。研究分为两个队列，主要队列纳入804例，FLOT队列纳入203例。患者入组后按1:1随机分为试验组和对照组，并基于地区（亚洲 vs 非亚洲）、肿瘤分期（II vs III vs Iva）、化疗方案（XP/FP vs FLOT）进行分层。主要终点设置为病理完全缓解率、无事件生存期、总生存期以及安全性（FLOT队列）。该研究已在ClinicalTrial.gov注册（编号NCT03221426），目前已完成招募。
研究结果：在2017年10月9号至2021年1月25号期间，1007例患者1：1随机纳入帕博利珠单抗+化疗组（n=502）和安慰剂+化疗组（n=505）。在主要队列中位随访47.7个月后，帕博利珠单抗组相比安慰剂组显著提升10.9%的pCR率（p < 0.00001）；无事件生存期有所增加但未达到预设统计学显著水平[44.4个月(95% CI: 33.0 - NA) vs 25.3个月(95%CI: 20.6 - 33.9); HR= 0.81, 95% CI: 0.67 - 0.99, p = 0.0198 > 0.0178]；总生存期没有明显获益[60.7个月vs 58个月(HR=0.90, 95%CI: 0.73 - 1.12, p = 0.174)]；两组不良事件发生率相当[3级及以上(78% vs 74%)；严重的治疗相关不良事件(26% vs 24%)]。
研究结论：在未经治疗的局部进展期胃或胃食管结合部腺癌患者中，新辅助/辅助帕博利珠单抗联合化疗可显著提高pCR率，但未能显著转化为EFS/OS生存获益。 |
| 英文摘要: |
| Background The benefit of combining chemotherapy and immune checkpoint inhibitors as neoadjuvant/adjuvant therapy in locally-advanced gastric and gastroesophageal junction cancer is unknown. The interim analysis of the KEYNOTE-585 reported the efficacy and safety of neoadjuvant/adjuvant pembrolizumab plus chemotherapy in patients with locally-advanced gastric and gastroesophageal junction cancer.
Methods The investigators conducted a randomized, double-blind, placebo-controlled phase III clinical study at 143 centers in 24 countries. The study recruited patients with age≥18 years, previously untreated and resectable locally-advanced gastric and gastroesophageal junction adenocarcinoma (≥T3 or N+). The study was divided into two cohorts, with 804 patients included in the Main cohort and 203 patients in the FLOT cohort. Patients were enrolled and randomized 1:1 into treatment and control groups. Randomization was stratified by region (Asian vs. no-Asian), tumor stage (II vs. III vs. IVa), and chemotherapy regimen (XP/FP vs. FLOT). The primary endpoints were set as pathologic complete remission rate, event-free survival, overall survival, and safety (FLOT cohort). The study was registered with ClinicalTrial.gov (No. NCT03221426) and recruitment has been completed.
Findings Between October 9, 2017 and January 25, 2021, 1007 patients were randomized 1:1 to the pembrolizumab plus chemotherapy group (n=502) and the placebo plus chemotherapy group (n=505). After a median follow-up of 47.7 months in the primary cohort, the treatment group significantly improved the pCR rate by 10.9% compared to the placebo group (p < 0.00001); event-free survival was increased but did not reach the pre-specified statistically significant level [44.4 months (95% CI: 33.0 - NA) vs. 25.3 months (95% CI: 20.6 - 33.9); HR= 0.81, 95% CI: 0.67 - 0.99, p = 0.0198 > 0.0178]; no significant benefit in overall survival [60.7 months vs 58 months (HR = 0.90, 95% CI: 0.73 - 1.12, p = 0.174)]. There is comparable incidence of adverse events in the two groups [grade 3 and above (78% vs 74%); serious treatment related adverse events (26% vs 24%).
Interpretation In untreated patients with locally-advanced gastric and gastroesophageal junction cancer, neoadjuvant/adjuvant pembrolizumab plus chemotherapy significantly increased the pCR rate but failed to significantly translate into survival benefit such as EFS/OS. |
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