EP4 Antagonist ONO-4578 Plus Nivolumab and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Negative Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer

초록

OBJECTIVE: EP4, a key receptor in the prostaglandin E2 axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. METHODS: This multicenter, double-blind, randomized phase II study enrolled chemotherapy-na&#xef;ve patients with human epidermal growth factor receptor 2 (HER2)-negative unresectable advanced or recurrent G/GEJC. Patients were randomly assigned (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), and safety. RESULTS: At the data cutoff, 226 patients were randomly assigned to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio [HR] of 0.67 [90% CI, 0.48 to 0.92]; P = .040 [prespecified two-sided &#x3b1; = .10]), with favorable OS at a prespecified analysis with limited follow-up (HR of 0.60 [95% CI, 0.37 to 0.96]) and ORR (62.0% v 48.7%). Exploratory subgroup analyses suggested that the ONO-4578 regimen provided greater benefit in PD-L1 combined positive score (CPS) &#x2265;1, whereas no clear benefit was observed in those with CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored the ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhea (55.7% v 45.3%) and anemia (55.0% v 34.7%). CONCLUSIONS: This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase III trial.