ONO-4578 (EP4 antagonist) + nivolumab + oxaliplatin/fluoropyrimidine extends PFS in 1L HER2-negative G/GEJ

ONO-4578 is an oral prostaglandin E2 (PGE2)–EP4 receptor antagonist intended to reverse myeloid-driven immunosuppression and potentially deepen anti–PD-1 benefit when added to nivolumab + chemotherapy. In the randomized, double-blind Phase 2 ONO-4578-08 trial (NCT06256328) across Japan/Korea/Taiwan, chemo-naïve HER2-negative unresectable adv/rec gastric/GEJ cancer patients received ONO-4578 40mg QD vs placebo (2:1) with nivolumab 360mg Q3W + SOX/CAPOX (n=226; 150 vs 76): median PFS 9.0 vs 6.9 months (HR 0.67; 90% CI 0.48–0.92; p=0.040), ORR 62.0% vs 48.7%, and early OS signal (not reached vs 12.7 months; HR 0.60; 95% CI 0.37–0.96) at ~8.5-month median follow-up. Safety looked directionally tougher on the triplet—diarrhea (55.7%), anemia (55.0%), neuropathy (50.3%) and serious TEAEs (53.7% vs 42.7%)—while efficacy benchmarks appear at least competitive with the current anti–PD-1+chemo backbone (e.g., pembrolizumab+chemo in KEYNOTE-859: median PFS 6.9 vs 5.6 months; ORR 51% vs 42%).