Journal Article

ONO‐4578 Plus Nivolumab in Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer

Kawazoe, Akihito, Yoshida, Kazuo, Oki, Eiji, Fukagawa, Takeo, Hosaka, Hisashi, Tsuji, Yasushi, Esaki, Taito, Hamamoto, Yasuo, Matsuoka, Hiroshi, Yamaguchi, Kensei, Hamaguchi, Tetsuya, Goto, Masahiro, Yoshida, Tomoko, Sugimoto, Naotoshi, Narita, Yukiya, Yokoyama, Fumiharu, Ishido, Kenji, Koeda, Keisuke, Oshima, Yoshiaki, Oshima, Takashi, Yasui, Hirofumi, Hara, Hiroki, Iwasa, Satoru, Nishina, Tomohiro, Boku, Shogen

2025

Overview

ONO‐4578, an EP4 antagonist, alone and combined with nivolumab, showed acceptable safety profiles and signs of antitumor activity in solid tumors. The expansion part examined the safety, preliminary efficacy, and biomarkers of ONO‐4578 plus nivolumab in unresectable advanced or recurrent gastric or gastroesophageal junction (G/GEJ) cancer. Patients were enrolled into three groups: with previous immuno‐oncology treatment (IO‐treated; n = 30), without IO treatment (IO‐naive; n = 30), and with UGT1A1 polymorphism (UGT1A1p; n = 6). Treatment‐related adverse events (TRAEs) occurred in 46 patients (grade 3–4 in 17), with no grade 5 events reported. We confirmed the tolerability of the treatment in UGT1A1p. Objective response and disease control rates were 10.0% and 73.3%, respectively, in IO‐treated and 16.7% and 40.0%, respectively, in IO‐naive. Biomarker analysis indicated immune activation in the tumor microenvironment after the treatment. In conclusion, ONO‐4578 plus nivolumab showed a manageable safety profile and antitumor activity in G/GEJ cancer. Trial Registration: Japan Registry of Clinical Trials number: jRCT2080223441; ClinicalTrials.gov identifier: NCT03155061 The limited efficacy of current immune checkpoint inhibitors requires new approaches to overcome immunosuppression. In this phase 1 study, ONO‐4578 plus nivolumab showed a manageable safety profile, signs of antitumor activity, and immune activation, providing reference for further studies evaluating the clinical benefit of ONO‐4578 and nivolumab in various cancers.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adult / Aged / Aged, 80 and over / Antibodies / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antitumor activity / Biomarkers / Cancer / Cancer therapies / Care and treatment / Clinical trials / Cytotoxicity / Disease control / Diseases / dose‐limiting toxicity / Drug dosages / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - genetics / Esophageal Neoplasms - pathology / Esophagogastric Junction - drug effects / Esophagogastric Junction - pathology / Female / Gastric cancer / Humans / Immune response / Lymphocytes / Male / Middle Aged / Mutation / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - pathology / nivolumab / Nivolumab - administration & dosage / Nivolumab - adverse effects / Nonsteroidal anti-inflammatory drugs / Oncology / Original / ORIGINAL ARTICLE / Patients / Pharmacokinetics / phase I / Polymorphism / prostaglandin E2 receptor EP4 / Relapse / Response rates / Solid tumors / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics / Stomach Neoplasms - pathology / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumors