EP4 Antagonist ONO-4578 Enhances Immunotherapy in Advanced HER2-Negative Gastric Cancer JCO | July 2026

Introduction:

Immune checkpoint inhibitors combined with platinum-based chemotherapy have become the standard first-line treatment for HER2-negative unresectable advanced or recurrent gastric and gastroesophageal junction (GEJ) cancers. However, many patients eventually develop resistance, highlighting the need for novel strategies to overcome the immunosuppressive tumour microenvironment. The Phase II ONO-4578 trial evaluated whether adding ONO-4578, an oral EP4 antagonist, to nivolumab and chemotherapy could improve treatment outcomes.

Why was this study needed?

Despite immunotherapy, long-term outcomes remain poor for advanced HER2-negative gastric and GEJ cancers.

The prostaglandin E2 (PGE2)-EP4 pathway suppresses antitumor immunity by promoting regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive macrophages.

Blocking EP4 may enhance the effectiveness of PD-1 inhibitors by restoring cytotoxic T-cell activity.

Early-phase studies demonstrated encouraging immune activation and acceptable safety with ONO-4578.

Randomized clinical evidence was needed to determine whether EP4 inhibition improves first-line treatment outcomes.

Results:

This randomized, double-blind Phase II trial enrolled 226 patients with HER2-negative unresectable advanced or recurrent gastric/GEJ cancer.

Adding ONO-4578 to nivolumab and oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) compared with standard immunochemotherapy.

The combination also demonstrated higher objective response rates, indicating greater tumor shrinkage.

Early overall survival analyses showed a favorable survival trend with ONO-4578, although longer follow-up is required for confirmation.

The greatest clinical benefit was observed in patients with PD-L1 combined positive score (CPS) ≥1, while limited benefit was seen in patients with CPS <1.

Treatment-related adverse events were generally manageable, with diarrhea and anemia being the most common toxicities, without introducing unexpected safety concerns.

Clinical Impact:

The ONO-4578 trial introduces EP4 inhibition as a promising new immunomodulatory strategy for advanced gastric and GEJ cancers. By targeting the PGE2–EP4 pathway, ONO-4578 appears to remodel the tumor microenvironment and enhance the activity of nivolumab plus chemotherapy. The results are particularly encouraging for patients with PD-L1 CPS ≥1, suggesting that dual immune modulation may represent the next evolution of first-line therapy. Confirmation in Phase III trials will determine whether EP4 antagonists become part of routine clinical practice.

Bottom Line:

Adding the oral EP4 antagonist ONO-4578 to nivolumab and chemotherapy significantly improved progression-free survival and response rates in HER2-negative advanced gastric and gastroesophageal junction cancers, particularly in patients with PD-L1 CPS ≥1. This novel immunotherapy combination represents a promising future first-line treatment strategy pending Phase III validation.