Multicenter phase 3 trial of first-line retlirafusp alfa plus chemotherapy for advanced HER2-negative G/GEJ adenocarcinoma

The multicenter phase 3 RELIGHT study in China evaluated the anti-PD-L1/TGF-beta bispecific antibody retlirafusp alfa plus standard chemotherapy as first-line treatment for unresectable, locally advanced or metastatic HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. A total of 731 patients with previously untreated disease were randomized 1:1 to receive intravenous retlirafusp alfa or placebo every three weeks; both groups with standard capecitabine plus oxaliplatin (CAPOX). The primary endpoint was overall survival (OS), assessed in patients with PD-L1 combined positive score (CPS) ≥ 5 and in the intention-to-treat (ITT) group. Addition of retlirafusp alfa to CAPOX was associated with significant prolongation of OS, both in patients with PD-L1 CPS ≥ 5 (median 16.8 versus 10.4 months; sHR 0.53; p<0.0001) and in the ITT group (15.8 versus 11.2 months; sHR 0.66; p<0.0001). Progression-free survival was also prolonged with addition of retlirafusp alfa to CAPOX in the PD-L1 CPS ≥ 5 group (sHR 0.52; 95% CI 0.42-0.66) and in the ITT group (sHR 0.57; 0.48-0.69). Grade ≥ 3 treatment-related adverse events were generally comparable between patients treated with retlirafusp alfa plus CAPOX (62.6%) and those treated with placebo plus CAPOX (59.0%). The authors conclude that retlirafusp alfa plus CAPOX is a first-line treatment option for unresectable advanced HER2-negative G/GEJ adenocarcinoma. A limitation is that chemotherapy alone served as comparator, given that the study protocol was finalized before PD-1 inhibitor plus chemotherapy became the approved standard-of-care regimen in China.