Retlirafusp Alfa Improves Overall Survival in Phase 3 Trial of HER2– Gastric Cancer

Retlirafusp alfa plus chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in patients with previously untreated, unresectable, locally advanced or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from the phase 3 RELIGHT trial (NCT04950322) published in the Journal of Clinical Oncology.¹

Among patients with a PD-L1 combined positive score (CPS) of 5 or higher, median OS was 16.8 months with retlirafusp alfa plus capecitabine and oxaliplatin (CAPOX) compared with 10.4 months with placebo plus CAPOX (HR, 0.53; 95% CI, 0.40-0.68; 1-sided P < .0001). In the overall intention-to-treat (ITT) population, median OS was 15.8 months vs 11.2 months, respectively (HR, 0.66; 95% CI, 0.53-0.81; 1-sided P < .0001).¹

The findings suggest that retlirafusp alfa may offer a new first-line treatment approach for patients with advanced HER2-negative gastric or GEJ adenocarcinoma.

RELIGHT Trial Design and Efficacy Findings

The randomized, double-blind phase 3 RELIGHT trial enrolled 731 patients with previously untreated, unresectable, locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma. Patients were randomly assigned 1:1 to receive intravenous retlirafusp alfa or placebo every 3 weeks, with both groups receiving CAPOX chemotherapy.

OS was the primary end point, evaluated in the overall population and specifically in patients with PD-L1 CPS of 5 or higher.

PFS also favored retlirafusp alfa plus chemotherapy. Among patients with PD-L1 CPS of 5 or higher, median PFS was 7.6 months with retlirafusp alfa plus CAPOX compared with 5.5 months with placebo plus CAPOX (HR, 0.52; 95% CI, 0.42-0.66). In the ITT population, median PFS was 7.0 months vs 5.5 months, respectively (HR, 0.57; 95% CI, 0.48-0.69).¹

Safety and Clinical Implications

Grade 3 or higher treatment-related adverse events occurred in 62.6% of patients receiving retlirafusp alfa plus CAPOX (228 of 364 patients) and 59.0% of patients receiving placebo plus CAPOX (n = 216/366). The investigators reported that rates of these adverse events were generally comparable between treatment groups.¹

Retlirafusp alfa is a bifunctional fusion protein designed to target both PD-L1 and TGF-β, 2 pathways involved in tumor immune evasion. By inhibiting PD-L1–mediated immune suppression and neutralizing TGF-β, the agent is intended to restore antitumor immune activity.²

One important limitation of RELIGHT is its comparator. The trial compared retlirafusp alfa plus CAPOX with placebo plus CAPOX, rather than with a PD-1 inhibitor plus chemotherapy. According to the investigators, the study protocol was finalized before PD-1 inhibitor plus chemotherapy became an approved standard-of-care regimen in China. This limits direct comparisons with contemporary immunotherapy-based treatment approaches.¹

Overall, RELIGHT demonstrated statistically significant improvements in OS and PFS with retlirafusp alfa plus CAPOX in patients with advanced HER2-negative gastric or GEJ adenocarcinoma. Further evaluation against contemporary treatment regimens will help clarify the agent’s potential role in first-line care.

REFERENCES

1. Peng Z, Wang J, Zhang Y, et al. 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). J Clin Oncol. Published online September 24, 2026. doi:10.1200/JCO-25-02933

2. National Cancer Institute. Retlirafusp alfa: NCI Drug Dictionary. Accessed October 15, 2026. https://tinyurl.com/muw68j2w