Background
Phase III, randomized, double-blind, placebo-controlled trial (RELIGHT) in 731 patients with previously untreated, unresectable locally advanced or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma, conducted in China. Retlirafusp alfa (SHR-1701) is a first-in-class bifunctional anti-PD-L1/TGF-βRII fusion protein (PD-L1 x TGF-β trap).
Results
Interventions and follow up: Arm A: Retlirafusp alfa IV q3wk + CAPOX (capecitabine + oxaliplatin)
Arm B: Placebo IV q3wk + CAPOX
Primary endpoint: OS, tested hierarchically in PD-L1 CPS≥5 population then ITT
mFollow up: NR
Results: OS (CPS≥5): 16.8 vs 10.4 mo, HR 0.53, 95% CI 0.40–0.68, one-sided P<.0001
OS (ITT): 15.8 vs 11.2 mo, HR 0.66, 95% CI 0.53–0.81, one-sided P<.0001
PFS (CPS≥5): 7.6 vs 5.5 mo, HR 0.52, 95% CI 0.42–0.66
PFS (ITT): 7.0 vs 5.5 mo, HR 0.57, 95% CI 0.48–0.69
Arm B: Placebo IV q3wk + CAPOX
Primary endpoint: OS, tested hierarchically in PD-L1 CPS≥5 population then ITT
mFollow up: NR
Results: OS (CPS≥5): 16.8 vs 10.4 mo, HR 0.53, 95% CI 0.40–0.68, one-sided P<.0001
OS (ITT): 15.8 vs 11.2 mo, HR 0.66, 95% CI 0.53–0.81, one-sided P<.0001
PFS (CPS≥5): 7.6 vs 5.5 mo, HR 0.52, 95% CI 0.42–0.66
PFS (ITT): 7.0 vs 5.5 mo, HR 0.57, 95% CI 0.48–0.69
Adverse events
Grade ≥3 treatment-related AE: 62.6% (retlirafusp alfa + CAPOX) vs 59.0% (placebo + CAPOX)
Event-level detail: NR in primary abstract; safety described as consistent with known CAPOX/anti-PD-L1 profile
Event-level detail: NR in primary abstract; safety described as consistent with known CAPOX/anti-PD-L1 profile
Conclusions
Adding retlirafusp alfa to first-line CAPOX significantly improved OS and PFS over chemotherapy alone in HER2-negative advanced gastric/GEJ adenocarcinoma, with the largest benefit in PD-L1 CPS≥5 tumors. This is the first phase III trial of a PD-L1/TGF-β bispecific to meet its primary endpoint, supporting retlirafusp alfa plus chemotherapy as a new first-line option.
Key Limitations
Comparator was chemotherapy alone, not chemotherapy plus a PD-1 inhibitor. The protocol was finalized before PD-1 inhibitor plus chemotherapy became the approved standard of care in China, so RELIGHT does not establish superiority over the current global first-line standard. Trial population was entirely Chinese, limiting generalizability. Grade ≥3 AE breakdown by event type was not reported in the primary abstract.
Clinical Context
Retlirafusp alfa plus fluoropyrimidine/platinum chemotherapy received NMPA (China) approval in January 2026 for first-line HER2-negative gastric/GEJ adenocarcinoma with PD-L1 CPS≥1, the first global approval of a PD-L1/TGF-β bispecific after earlier clinical failures of this drug class (e.g., bintrafusp alfa/M7824). No FDA or EMA filing yet. NCCN, ASCO, and ESMO currently recommend chemotherapy plus a PD-1 inhibitor (nivolumab per CheckMate-649, or pembrolizumab per KEYNOTE-859) as first-line standard of care in this population; retlirafusp alfa has not been tested against that active comparator, so its place relative to established PD-1 inhibitor regimens outside China is undefined.
References