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

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

doi:10.1111/cas.70130

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

Cancer Sci. 2025 Sep;116(9):2523-2536. doi: 10.1111/cas.70130. Epub 2025 Jul 6.

Authors

Akihito Kawazoe¹, Kensei Yamaguchi², Tetsuya Hamaguchi³, Yukiya Narita⁴, Shogen Boku⁵, Takashi Oshima⁶, Hiroki Hara⁷, Yasuo Hamamoto⁸, Kenji Ishido⁹, Taito Esaki¹⁰, Hisashi Hosaka¹¹, Hirofumi Yasui¹², Keisuke Koeda¹³, Tomohiro Nishina¹⁴, Yasushi Tsuji¹⁵, Takeo Fukagawa¹⁶, Masahiro Goto¹⁷, Eiji Oki¹⁸, Naotoshi Sugimoto¹⁹, Hiroshi Matsuoka²⁰, Fumiharu Yokoyama²¹, Tomoko Yoshida²², Kazuo Yoshida²³, Yoshiaki Oshima²⁴, Satoru Iwasa²⁵

Affiliations

¹ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
² Department Director of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
³ Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Saitama, Japan.
⁴ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁵ Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, Japan.
⁶ Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
⁷ Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan.
⁸ Keio Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
⁹ Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan.
¹⁰ Department of Gastrointestinal and Medical Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan.
¹¹ Department of Gastroenterology, Gunma Prefectural Cancer Center, Ota-shi, Gunma, Japan.
¹² Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
¹³ Department of Medical Safety Science, Iwate Medical University School of Medicine, Shiwa, Japan.
¹⁴ Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan.
¹⁵ Department of Medical Oncology, Tonan Hospital, Sapporo, Japan.
¹⁶ Department of Surgery, School of Medicine Teikyo University, Tokyo, Japan.
¹⁷ Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan.
¹⁸ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁹ Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan.
²⁰ Department of Surgery, Fujita Health University, Toyoake, Aichi, Japan.
²¹ Translational Research Group, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²² Bioinformatics Group, Drug Discovery Tech, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²³ Statistical Analysis Section, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²⁴ Oncology Early Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²⁵ Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Abstract

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.

Keywords: dose‐limiting toxicity; gastric cancer; nivolumab; phase I; prostaglandin E2 receptor EP4.

Publication types

Clinical Trial, Phase I
Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols* / adverse effects
Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
Esophageal Neoplasms* / drug therapy
Esophageal Neoplasms* / genetics
Esophageal Neoplasms* / pathology
Esophagogastric Junction* / drug effects
Esophagogastric Junction* / pathology
Female
Humans
Male
Middle Aged
Neoplasm Recurrence, Local* / drug therapy
Neoplasm Recurrence, Local* / pathology
Nivolumab* / administration & dosage
Nivolumab* / adverse effects
Stomach Neoplasms* / drug therapy
Stomach Neoplasms* / genetics
Stomach Neoplasms* / pathology
Tumor Microenvironment / drug effects

Substances

Nivolumab

Associated data

ClinicalTrials.gov/NCT03155061

Grants and funding

Ono Pharmaceutical