围手术期度伐利尤单抗治疗胃癌和胃食管交界癌

Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer.

作者信息

Janjigian Yelena Y, Al-Batran Salah-Eddin, Wainberg Zev A, Muro Kei, Molena Daniela, Van Cutsem Eric, Hyung Woo Jin, Wyrwicz Lucjan, Oh Do-Youn, Omori Takeshi, Moehler Markus, Garrido Marcelo, Oliveira Sulene C S, Liberman Moishe, Oliden Victor Castro, Smyth Elizabeth C, Stein Alexander, Bilici Mehmet, Alvarenga Maria Lorena, Kozlov Vadim, Rivera Fernando, Kawazoe Akihito, Serrano Olivier, Heilbron Eric, Negro Alejandra, Kurland John F, Tabernero Josep

机构信息

Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York.

Krankenhaus Nordwest, University Cancer Center (UCT) Frankfurt, and Frankfurt Institute of Clinical Cancer Research (IKF), Frankfurt, Germany.

出版信息

N Engl J Med. 2025 Jun 1. doi: 10.1056/NEJMoa2503701.

DOI:10.1056/NEJMoa2503701

PMID:40454643

Abstract

BACKGROUND

Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is a standard therapy for resectable gastric and gastroesophageal junction adenocarcinomas, but recurrence rates remain high. Immunotherapy plus chemotherapy may improve outcomes.

METHODS

In a phase 3, multinational, double-blind, randomized trial, we assigned participants with resectable gastric or gastroesophageal junction adenocarcinoma, in a 1:1 ratio, to receive durvalumab at a dose of 1500 mg or placebo every 4 weeks plus FLOT for 4 cycles (2 cycles each of neoadjuvant and adjuvant therapy), followed by durvalumab or placebo every 4 weeks for 10 cycles. The primary end point was event-free survival; secondary end points included overall survival and pathological complete response.

RESULTS

A total of 474 participants were randomly assigned to the durvalumab group, and 474 to the placebo group (median follow-up, 31.5 months; interquartile range, 26.7 to 36.6). Two-year event-free survival (Kaplan-Meier estimate) was 67.4% among the participants in the durvalumab group and 58.5% among those in the placebo group (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001). Two-year overall survival was 75.7% in the durvalumab group and 70.4% in the placebo group (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], and during the period from month 12 onward, 0.67 [95% CI, 0.50 to 0.90]; P = 0.03 by a stratified log-rank test [exceeding the significance threshold of P<0.0001]). The percentage of participants with a pathological complete response was 19.2% in the durvalumab group and 7.2% in the placebo group (relative risk, 2.69 [95% CI, 1.86 to 3.90]). Adverse events with a maximum grade of 3 or 4 were reported in 340 participants (71.6%) in the durvalumab group and in 334 (71.2%) in the placebo group. The percentage of participants with delayed surgery was 10.1% and 10.8%, respectively, and the percentage with delayed initiation of adjuvant treatment was 2.3% and 4.6%.

CONCLUSIONS

Perioperative durvalumab plus FLOT led to significantly better event-free survival outcomes than FLOT alone among participants with resectable gastric or gastroesophageal junction adenocarcinoma. (Funded by AstraZeneca; MATTERHORN ClinicalTrials.gov number, NCT04592913.).

摘要

背景

围手术期氟尿嘧啶、亚叶酸钙、奥沙利铂和多西他赛（FLOT）方案是可切除胃及胃食管交界腺癌的标准治疗方案，但复发率仍然很高。免疫治疗联合化疗可能改善治疗效果。

方法

在一项3期、多中心、双盲、随机试验中，我们将可切除胃或胃食管交界腺癌患者按1:1的比例随机分配，每4周接受一次1500mg度伐利尤单抗或安慰剂治疗，同时接受4个周期的FLOT方案（新辅助和辅助治疗各2个周期），之后每4周接受度伐利尤单抗或安慰剂治疗，共10个周期。主要终点是无事件生存期；次要终点包括总生存期和病理完全缓解率。

结果

共有474名参与者被随机分配到度伐利尤单抗组，474名被分配到安慰剂组（中位随访时间31.5个月；四分位间距26.7至36.6个月）。度伐利尤单抗组参与者的两年无事件生存率（Kaplan-Meier估计值）为67.4%，安慰剂组为58.5%（事件或死亡风险比为0.71；95%置信区间[CI]为0.58至0.86；P<0.001）。度伐利尤单抗组的两年总生存率为75.7%，安慰剂组为70.4%（0至12个月期间死亡的分段风险比为0.99[95%CI为0.70至1.39]，12个月及以后期间为0.67[95%CI为0.50至0.90]；通过分层对数秩检验，P = 0.03[超过显著性阈值P<0.0001]）。病理完全缓解的参与者百分比在度伐利尤单抗组为19.2%，在安慰剂组为7.2%（相对风险为2.69[95%CI为1.86至3.90]）。度伐利尤单抗组340名参与者（71.6%）和安慰剂组334名参与者（71.2%）报告了最高3级或4级不良事件。延迟手术的参与者百分比分别为10.1%和10.8%，延迟开始辅助治疗的百分比分别为2.3%和4.6%。