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.