DOI: 10.1200/jco-25-02933 ISSN: 0732-183X

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)

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