对于局部进展期可切除的胃或胃食管结合部腺癌(gastric or gastroesophageal junction adenocarcinoma,GC/GEJC),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.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GC/GEJC患者中的疗效及安全性.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3期临床研究.研究招募了年龄≥18岁、既往未经治疗且可切除的局部进展期GC/GEJC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(ⅡvsⅢvsⅣa)、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.在2017年10月9日至2021年1月25日期间,1 007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).主要队列中位随访47.7个月后,帕博利珠单抗+化疗组相比安慰剂+化疗组病理完全缓解率显著提升10.9％(P＜0.001);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～NR)vs 25.3个月(95％CI:20.6～33.9),HR=0.81,95％CI:0.67～0.99,P=0.019 8];总生存期无明显获益(60.7个月vs 58.0个月,HR=0.90,95％CI:0.73～1.12,P=0.174).此外,两组安全性事件方面相似,包括3级及以上不良事件(78％vs 74％)和治疗相关严重不良事件(26％vs 24％)发生率.在未经治疗的局部进展期GC/GEJC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.
Interpretation of an Interim Analysis of the KEYNOTE-585 Study:Efficacy and Safety of Neoadjuvant/Adjuvant Pembrolizumab plus Chemotherapy in Locally-Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
The benefit of chemotherapy plus immune checkpoint inhibitors as neoadjuvant/adjuvant therapy in locally-advanced gastric or gastroesophageal junction adenocarcinoma(GC/GEJC)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 GC/GEJC.The investigators conducted a randomized,double-blind,placebo-controlled phase 3 clinical trial at 143 centers in 24 countries.The study recruited patients with age≥18 years old,previously untreated and resectable locally-advanced GC/GEJC(≥T3 or N+).The study was divided into two cohorts,with 804 patients in-cluded in the main cohort and 203 patients in the FLOT cohort.Patients were enrolled and randomized 1∶1 into treat-ment and control groups.Randomization was stratified by region(Asia vs non-Asia),tumor stage(Ⅱ vs Ⅲ vs Ⅳ a),and chemotherapy regimen(XP/FP vs FLOT).The primary endpoints were pathological complete response(pCR),event-free survival,overall survival,and safety(FLOT cohort).The study was registered with ClinicalTrial.gov(No.NCT03221426)and recruitment has been completed.Between October 9,2017 and January 25,2021,1 007 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＜0.001);event-free survival was increased but did not reach the pre-specified statistically significant level[44.4 months(95％CI:33.0～NR)vs 25.3 months(95％CI:20.6～33.9),HR=0.81,95％CI:0.67～0.99,P=0.019 8];no significant benefit in overall survival(60.7 months vs 58.0 months,HR=0.90,95％CI:0.73～1.12,P=0.174).In addition,there is similar incidence of safety events in the two groups,including adverse events grade≥3(78％vs 74％)and treatment-related serious adverse events(26％vs 24％).In untreated patients with locally-advanced GC/GEJC,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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