ONO-4578, a selective oral EP4 antagonist, in combination with nivolumab and chemotherapy has demonstrated a statistically significant improvement in progression-free survival compared with placebo plus nivolumab and chemotherapy in patients with previously untreated, HER2-negative, unresectable advanced or recurrent gastric/gastroesophageal junction cancer. The positive results from the phase 2 ONO-4578-08 trial met the study's primary endpoint, representing a potential advancement in first-line treatment for this challenging malignancy.
Novel Mechanism Targets Tumor Immune Suppression
ONO-4578 represents a novel approach to cancer immunotherapy through its selective antagonism of the prostaglandin E2 (PGE2) receptor EP4. PGE2, produced by tumor cells, 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.
The drug's mechanism addresses a key resistance pathway in cancer immunotherapy, potentially enhancing the efficacy of checkpoint inhibitors like nivolumab by removing immunosuppressive signals within the tumor microenvironment.
Phase 2 Trial Design and Patient Population
The ONO-4578-08 study is a multicenter, randomized clinical trial conducted across Japan, South Korea, and Taiwan. 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 required to have available tumor tissue samples for biomarker and translational analyses. Patients were excluded if they were unable to take oral medications, had HER2-positive tumors, active or historical autoimmune diseases such as rheumatoid arthritis, or were experiencing headache or nausea related to brain metastases.
Treatment Protocol and Dosing
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. Chemotherapy regimens consisted of either S-1 (tegafur-gimeracil-oteracil potassium) plus oxaliplatin or capecitabine plus oxaliplatin, administered according to regional standards of care.
Treatment continued until disease progression or the development of unacceptable toxicity. The primary endpoint was progression-free survival assessed by blinded independent central review, with key secondary endpoints including overall survival, objective response rate, duration of response, disease control rate, time to response, and safety and tolerability.
Safety Profile and Previous Clinical Experience
No new safety signals were identified in the trial with the addition of ONO-4578 to nivolumab and chemotherapy. These findings build upon earlier results from a phase 1 study of ONO-4578 plus nivolumab in heavily pretreated gastric cancer, which demonstrated antitumor activity and a manageable safety profile.
Addressing Significant Medical Need
Gastric cancer represents a substantial global health burden, with approximately 968,000 new cases diagnosed worldwide annually and approximately 660,000 deaths per year. In Japan, gastric cancer is the third most common type of cancer following colorectal cancer and lung cancer, with approximately 126,000 new cases and 43,000 deaths per year.
While combination therapies with anti-PD-1 antibody and chemotherapy have been approved for first-line treatment of HER2-negative unresectable advanced or recurrent gastric cancer as the standard treatment, unresectable gastric cancer remains incurable, creating a significant need for new treatment options.
Future Development Plans
Currently, a phase 2 randomized, open-label, multicenter trial is enrolling patients to evaluate the safety and efficacy of two dose levels of ONO-4578 in combination with nivolumab, modified FOLFOX6, and bevacizumab 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.
Detailed results from the phase 2 gastric cancer trial will be presented at an upcoming academic meeting, providing further insight into the clinical potential of this novel EP4 antagonist approach in oncology.
