First-Line Retlirafusp Alfa Plus Chemotherapy for Human Epidermal Growth Factor Receptor 2–Negative Gastric or Gastroesophageal Junction Adenocarcinoma: A Randomized, Double-Blind, Phase III Study (RELIGHT)

PURPOSE To evaluate retlirafusp alfa (an anti–PD-L1/transforming growth factor-β bispecific antibody) plus standard chemotherapy as first-line treatment for unresectable, locally advanced or metastatic, human epidermal growth factor receptor 2 (HER2)–negative gastric or gastroesophageal junction adenocarcinoma in the first-line setting. METHODS In this randomized, double-blind (RELIGHT), phase III study, 731 patients with previously untreated, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma were randomly assigned (1:1) to receive retlirafusp alfa or placebo intravenously every 3 weeks plus capecitabine and oxaliplatin (CAPOX). The primary end point was overall survival (OS), assessed in patients with PD-L1 combined positive score (CPS) ≥5 and the intention-to-treat analysis set. RESULTS Retlirafusp alfa plus CAPOX significantly prolonged OS versus placebo plus CAPOX in both patients with PD-L1 CPS ≥5 (median, 16.8 vs 10.4 months; stratified hazard ratio [HR], 0.53 [95% CI, 0.40-0.68]; one-sided P < .0001) and the intention-to-treat analysis set (median, 15.8 vs 11.2 months; stratified HR, 0.66 [95% CI, 0.53-0.81]; one-sided P < .0001). Progression-free survival benefit was observed with retlirafusp alfa plus CAPOX versus placebo plus CAPOX in both patients with PD-L1 CPS ≥5 (median, 7.6 v 5.5 months; stratified HR, 0.52 [95% CI, 0.42 to 0.66]) and the intention-to-treat analysis set (median, 7.0 v 5.5 months; stratified HR, 0.57 [95% CI, 0.48 to 0.69]). Grade ≥3 treatment-related adverse events were generally comparable between patients treated with retlirafusp alfa plus CAPOX (62.6% [228 of 364]) and those treated with placebo plus CAPOX (59.0% [216 of 366]). CONCLUSION Retlirafusp alfa plus CAPOX represents a first-line treatment option for unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma. A key limitation is that chemotherapy alone served as the comparator, given that the study protocol was finalized before PD-1 inhibitor plus chemotherapy became the approved standard-of-care regimen in China.

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Journal
Journal of Clinical Oncology
Published
2026-09-24
DOI
https://doi.org/10.1200/jco-25-02933
Primary Topic
Gastric Cancer Management and Outcomes
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article
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article

First-Line Retlirafusp Alfa Plus Chemotherapy for Human Epidermal Growth Factor Receptor 2–Negative Gastric or Gastroesophageal Junction Adenocarcinoma: A Randomized, Double-Blind, Phase III Study (RELIGHT)

Jun Zhang, Yanhong Deng, 牛作兴, Changlu Hu et al.
Journal of Clinical Oncology
Gastric Cancer Management and Outcomes
article

First-Line Retlirafusp Alfa Plus Chemotherapy for Human Epidermal Growth Factor Receptor 2–Negative Gastric or Gastroesophageal Junction Adenocarcinoma: A Randomized, Double-Blind, Phase III Study (RELIGHT)

Jun Zhang, Yanhong Deng, 牛作兴, Changlu Hu, Lin Shen, Yigui Chen, Zhongtao Zhang, Zhigao Wang, Zhi Peng, Jun Yao, Xizhi Zhang, Xiaodong Zhu, Jufeng Wang, Qun Zhao, Zhenyang Liu, Yan Chen, Wenliang Wang, Junsheng Wang, Jingdong Zhang, Kangsheng Gu, Ping Zhao, Shaozhong Wei, Hongxia Han, Jun Bai, Mingjun Zhang, Wenhui Yang, Yueyin Pan, Hongli Li, Yanqiao Zhang, Lin Xie
article en

Abstract

PURPOSE To evaluate retlirafusp alfa (an anti–PD-L1/transforming growth factor-β bispecific antibody) plus standard chemotherapy as first-line treatment for unresectable, locally advanced or metastatic, human epidermal growth factor receptor 2 (HER2)–negative gastric or gastroesophageal junction adenocarcinoma in the first-line setting. METHODS In this randomized, double-blind (RELIGHT), phase III study, 731 patients with previously untreated, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma were randomly assigned (1:1) to receive retlirafusp alfa or placebo intravenously every 3 weeks plus capecitabine and oxaliplatin (CAPOX). The primary end point was overall survival (OS), assessed in patients with PD-L1 combined positive score (CPS) ≥5 and the intention-to-treat analysis set. RESULTS Retlirafusp alfa plus CAPOX significantly prolonged OS versus placebo plus CAPOX in both patients with PD-L1 CPS ≥5 (median, 16.8 vs 10.4 months; stratified hazard ratio [HR], 0.53 [95% CI, 0.40-0.68]; one-sided P < .0001) and the intention-to-treat analysis set (median, 15.8 vs 11.2 months; stratified HR, 0.66 [95% CI, 0.53-0.81]; one-sided P < .0001). Progression-free survival benefit was observed with retlirafusp alfa plus CAPOX versus placebo plus CAPOX in both patients with PD-L1 CPS ≥5 (median, 7.6 v 5.5 months; stratified HR, 0.52 [95% CI, 0.42 to 0.66]) and the intention-to-treat analysis set (median, 7.0 v 5.5 months; stratified HR, 0.57 [95% CI, 0.48 to 0.69]). Grade ≥3 treatment-related adverse events were generally comparable between patients treated with retlirafusp alfa plus CAPOX (62.6% [228 of 364]) and those treated with placebo plus CAPOX (59.0% [216 of 366]). CONCLUSION Retlirafusp alfa plus CAPOX represents a first-line treatment option for unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma. A key limitation is that chemotherapy alone served as the comparator, given that the study protocol was finalized before PD-1 inhibitor plus chemotherapy became the approved standard-of-care regimen in China.

Journal of Clinical Oncology
Hebei Medical University (CN), Central South University (CN), Harbin Medical University (CN), Sun Yat-sen University (CN), Shanxi Medical University (CN), Shanghai Jiao Tong University (CN), Capital Medical University (CN), Anhui Medical University (CN), Peking University (CN), Kunming Medical University (CN), Ruijin Hospital (CN), Tianjin Medical University Cancer Institute and Hospital (CN), Fudan University Shanghai Cancer Center (CN), Sixth Affiliated Hospital of Sun Yat-sen University (CN), Peking University Cancer Hospital (CN), Jilin Province Tumor Hospital (CN), Shandong Tumor Hospital (CN), Shanxi Provincial Cancer Hospital (CN), Third Affiliated Hospital of Harbin Medical University (CN), Fourth Hospital of Hebei Medical University (CN), Hunan Cancer Hospital (CN), Sichuan Cancer Hospital (CN), Anhui Provincial Hospital (CN), First Affiliated Hospital of Henan University of Science and Technology (CN), First Affiliated Hospital of Anhui Medical University (CN), Northern Jiangsu People's Hospital (CN), Henan Cancer Hospital (CN), Beijing Friendship Hospital (CN), Jiangsu Hengrui Medicine (China) (CN), Fujian Provincial Cancer Hospital (CN), Second Affiliated Hospital of Anhui Medical University (CN), Shanxi Provincial People’s Hospital (CN), Hubei Cancer Hospital (CN), Liaoning Cancer Hospital & Institute (CN), Anyang Tumor Hospital (CN), Shandong First Medical University (CN)
Good health and well-being
Openalex Percentile: Top 11%
Gastric Cancer Management and Outcomes
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