Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer
Authors: Xu Jianming , Jiang Haiping , Pan Yueyin , Gu Kangsheng , Cang Shundong , Han Lei , Shu Yongqian , Li Jiayi , Zhao Junhui , Pan Hongming , Luo Suxia , Qin Yanru , Guo Qunyi , Bai Yuxian , Ling Yang , Yang Jianwei , Yan Zhilong , Yang Lei , Tang Yong , He Yifu , Zhang Liangming , Liang Xinjun , Niu Zuoxing , Zhang Jingdong , Mao Yong , Guo Yingmei , Peng Bo , Li Ziran , Liu Ying , Wang Yan , Zhou Hui ,   ORIENT-16 Investigators, Sun Hongmei , Wang Qi , Li Junhe , Jiang Da , Guo Weijian , Ying Jieer , Wang Shubin , Zang Aimin , Cai Shirong , Hu Chunhong , Zhang Tao , Tao Min , Liang Jun , Mao Qinsheng , Zhang Minghui , Mao Rui , Yang Hui , Zhang Hongyu , Shen Lin , Lu Jin , Li Wenxin , Chen Yamin , Chen Lei , Zhuang Zhixiang , Bai Chunmei , Liu Heli , Chen Jingtang , Liao Wangjun , Qiu Meng , Song Rongfeng , Li Man , Qian Suying , Liu Yunpeng , Liu Jiang , Wang Dong , Yin Xianli , Huang Zhiming 
Published: December 2023

ImportanceGastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy.ObjectiveTo compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100).Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021.InterventionsPatients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years.Main Outcomes and MeasuresThe primary end point was overall survival time from randomization.ResultsOf the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (&amp;lt;0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%).Conclusions and RelevanceAmong patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT03745170