ONO-4578 (EP4/PGE2-axis antagonist) + nivolumab + oxaliplatin chemo improves PFS in 1L HER2-negative gastric/GEJ cancer

ONO-4578 is an oral, selective EP4 antagonist designed to blunt PGE2-driven tumor immunosuppression and potentially deepen anti–PD-1 activity when combined with nivolumab. In this multicenter, double-blind, randomized Phase II trial in chemotherapy-naïve HER2-negative unresectable advanced or recurrent gastric/gastroesophageal junction cancer (n=226; 2:1 randomization), ONO-4578 + nivolumab + oxaliplatin-based chemotherapy improved investigator-assessed PFS vs placebo + nivolumab + chemotherapy (HR 0.67; 90% CI 0.48–0.92; p=0.040; prespecified two-sided α=0.10), with higher ORR (62.0% vs 48.7%) and an early OS signal (HR 0.60; 95% CI 0.37–0.96) that became “numerically favorable” with ≥16.1 months minimum follow-up. Diarrhea (55.7% vs 45.3%) and anemia (55.0% vs 34.7%) were more common with ONO-4578; exploratory subgroup data suggested benefit concentrated in PD-L1 CPS ≥1, aligning with the current PD-1 + chemo standard where CPS <1 has limited incremental benefit and CPS ≥1 comprises the majority of patients (~82% in CheckMate 649).