ONO-4578 Plus Nivolumab/Chemo Improves PFS in HER2– Advanced Gastric Cancer

ONO-4578, a selective oral EP4 antagonist, given in combination with nivolumab (Opdivo) and chemotherapy, demonstrated a statistically significant improvement in progression-free survival (PFS) compared with placebo plus nivolumab and chemotherapy in patients with previously untreated, HER2-negative, unresectable advanced or recurrent gastric/gastroesophageal junction (GEJ) cancer, meeting the primary end point of the phase 2 ONO-4578-08 trial (NCT06256328).1

ONO-4578 is a selective, oral antagonist of the prostaglandin E2 (PGE2) receptor EP4. PGE2 is produced by tumor cells and suppresses antitumor immunity via EP4 receptor signaling on immune cells. By blocking this pathway, ONO-4578 is designed to restore immune activity and augment the antitumor effects of PD-1 blockade.

No new safety signals were identified in the trial with the addition of ONO-4578 to nivolumab and chemotherapy.

These findings follow earlier results from a phase 1 study of ONO-4578 plus nivolumab in heavily pretreated gastric cancer, which also demonstrated antitumor activity and a manageable safety profile.2 Detailed results from the phase 2 trial will be presented at an upcoming academic meeting.1

What is the design of the phase 2 ONO-4578-08 trial?

ONO-4578-08 is a multicenter, randomized clinical trial being conducted across Japan, South Korea, and Taiwan. The study enrolled patients with previously untreated, HER2-negative, unresectable advanced or recurrent gastric cancer, including gastroesophageal junction cancer.3

The study enrolled patients with histologically confirmed adenocarcinoma of the stomach or esophagogastric junction who had not received prior systemic chemotherapy for unresectable advanced or recurrent disease. Eligible participants were also required to have available tumor tissue samples for biomarker and translational analyses.

Patients were excluded if they were unable to take oral medications or had HER2-positive tumors. Individuals with active or historical autoimmune diseases, such as rheumatoid arthritis, were not eligible, nor were patients experiencing headache or nausea related to brain metastases.

Patients were randomly assigned to receive ONO-4578 in combination with nivolumab and chemotherapy; or placebo in combination with nivolumab and chemotherapy. Chemotherapy regimens consisted of either S-1 (tegafur-gimeracil-oteracil potassium) plus oxaliplatin or capecitabine plus oxaliplatin, administered according to regional standards of care.1,3

In the experimental arm, patients received oral ONO-4578 at a dose of 40 mg once daily and nivolumab 360 mg intravenously every 3 weeks, in combination with chemotherapy.1 Treatment continued until disease progression or the development of unacceptable toxicity.

The primary end point was PFS assessed by blinded independent central review (BICR). Key secondary end points included overall survival, objective response rate, duration of response, disease control rate, time to response, and safety and tolerability. Additional measures included pharmacokinetic parameters and the incidence of anti-drug antibodies.

What future evaluations are planned for ONO-4578?

Currently, a phase 2 randomized, open-label, multicenter trial (NCT06948448) is enrolling patients to evaluate the safety and efficacy of two dose levels of ONO-4578 in combination with nivolumab, modified FOLFOX6, and bevacizumab (Avastin) compared with standard-of-care therapy as first-line treatment for patients with non–microsatellite instability–high/mismatch repair–deficient, PD-L1–positive advanced colorectal cancer.4

References

1. Ono announces ONO-4578 (EP4 antagonist) in combination with Opdivo and chemotherapy met the primary endpoint in a phase 2 clinical trial in patients with certain gastric cancer. News Release. Ono Pharmaceutical. October 9, 2025. Accessed October 9, 2025. https://www.ono-pharma.com/en/news/20251009_2.html
2. Kawazoe A, Yamaguchi K, Hamaguchi T, et al. ONO‐4578 plus nivolumab in unresectable advanced or recurrent gastric or gastroesophageal junction cancer. Cancer Sci. 2025;116(9):2523-2536. doi:10.1111/cas.70130
3. A study to investigate the efficacy and safety of ONO-4578 in combination with nivolumab and chemotherapy in chemotherapy-naïve participants with HER2-negative unresectable advanced or recurrent gastric cancer (including esophagogastric junction cancer). Clinicaltrials.gov. Updated July 29, 2024. Accessed October 9, 2025. https://clinicaltrials.gov/study/NCT06256328
4. A study to evaluate the safety and efficacy of two dose levels of ONO-4578 with Opdivo, in combination with mFOLFOX6 and bevacizumab versus standard of care in participants with non–MSI-H/dMMR, PD-L1–positive advanced colorectal cancer. Clinicaltrials.gov. Updated April 29, 2025. Accessed October 9, 2025. https://clinicaltrials.gov/study/NCT06948448