EP4 Antagonist ONO-4578 Plus Nivolumab and Chemotherapy in HER2-Negative Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer

PURPOSE: axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. PATIENTS AND METHODS: This multicenter, double-blind, randomized phase 2 study enrolled chemotherapy-naïve patients with HER2-negative unresectable advanced or recurrent G/GEJC. Patients were randomized (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. RESULTS: At the data cutoff, 226 patients were randomized to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio of 0.67; 90% confidence interval, 0.48-0.92; p-value, 0.040 prespecified two-sided α = 0.10), with favorable OS at a prespecified analysis with limited follow-up (hazard ratio of 0.60; 95% confidence interval, 0.37-0.96) and ORR (62.0% vs 48.7%). Exploratory subgroup analyses suggested that ONO-4578 regimen provided greater benefit in PD-L1 CPS ≥1, whereas no clear benefit in CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhoea (55.7% vs 45.3%), and anaemia (55.0% vs 34.7%). CONCLUSION: This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase 3 trial.