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A phase 2 clinical trial (NCT06256328)¹ for patients with previously untreated HER2-negative unresectable advanced or recurrent gastric cancer found that a combination of ONO-4578, an EP4 antagonist, and nivolumab (Opdivo), an anti–PD-1 antibody, resulted in statistically significant prolongation of progression-free survival (PFS). Full results will be announced at an upcoming academic meeting.²

What is the Phase 2 Study Investigating?

The multicenter, randomized phase 2 clinical trial, conducted by Ono Pharmaceutical Co, took place in 63 locations across Japan, South Korea, and Taiwan. There were 210 patients enrolled who received 40 mg of ONO-4578 once daily and 360 mg of nivolumab every 3 weeks in combination with chemotherapy, until disease progression or unacceptable toxicity was observed. This treatment was compared with placebo in combination with nivolumab and chemotherapy. The primary end point of PFS was met. No new safety concerns were identified in the trial.^1,2

Secondary end points included overall survival (OS), objective response rate (ORR), best overall response (BOR), duration of response (DOR), disease control rate (DCR), time to response (TTR), the maximum percent of change in the sum of diameters of the target lesions, and PFS after the next line of therapy, all measured up to 2 years.¹

Treatment for ONO-4578 and nivolumab and chemotherapy included a daily dose of ONO-4578, oxaliplatin on specified days, capecitabine on specified days, S-1 on specified days, and nivolumab on specified days. Treatment for placebo and nivolumab and chemotherapy also consisted of oxaliplatin, capecitabine, S-1, nivolumab, and a placebo drug daily.¹

What Patients Were Eligible?

To be eligible for the study, patients must have been diagnosed with esophagogastric junction cancer, be able to provide tumor tissue samples, and have not been treated with systemic chemotherapy as first-line therapy.¹

Exclusion criteria included being unable to take oral medicines; having HER2-positive disease; having contraindications to nivolumab, oxaliplatin, S-1, or capecitabine; having a history of severe drug-related adverse reactions caused by NSAIDs; having a history of concurrent autoimmune disease; and getting headaches and/or nausea associated with brain metastasis.¹

What Is the Mechanism of Action of ONO-4578?

ONO-4578 is a selective oral antagonist of EP4. Its primary function is to exert an antitumor effect by suppressing EP4 mediated effects of PGE₂ and by restoring cancer immunity. EP4 is one of the prostaglandins E2 (PGE₂) receptors.^1,2

In the phase 1 clinical trial (NCT03155061)³ in patients with unresectable advanced or recurrent gastric cancer, including gastroesophageal junction cancer, the combination of ONO-4578 and nivolumab showed antitumor effect and a manageable safety profile after the third-line or later treatment.

What Are the Next Steps in Research?

Ono is conducting several other clinical studies of ONO-4578, including a global phase 1 trial (NCT06547385)⁴ in patients with colorectal cancer. The open-label, uncontrolled study of approximately 40 patients is meant to evaluate the tolerability and safety of combination of ONO-4578 and ONO-4538 and the standard-of-care XELOX plus bevacizumab (Avastin), or the safety of ONO-4578 with ONO-4538 and the standard-of-care FOLFOX plus bevacizumab as first-line therapy, in patients with unresectable, advanced, or recurrent colorectal cancer. Ono is also evaluating the efficacy of ONO-4578 in patients with lung and breast cancer in other clinical trials.

REFERENCES:

1. 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 10, 2025. https://clinicaltrials.gov/study/NCT06256328

2. 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 Pharma. Published October 9, 2025. Accessed October 10, 2025. https://www.ono-pharma.com/en/news/20251009_2.html

3. Study of ONO-4578 With and Without ONO-4538 in Subjects Advanced or Metastatic Solid Tumors. ClinicalTrials.gov. Updated June 5, 2025. Accessed October 10, 2025. https://clinicaltrials.gov/study/NCT03155061

4. Study of ONO-4578 and XELOX/FOLFOX Plus Bevacizumab in Colorectal Cancer. ClinicalTrials.gov. Updated August 9, 2024. Accessed October 10, 2025. https://clinicaltrials.gov/study/NCT06547385