1546P - Safety, efficacy, and biomarkers for ONO-4578 plus nivolumab in unresectable advanced or recurrent gastric or gastroesophageal cancer

Background

Prostaglandin E₂ (PGE₂) and its receptor EP4 showed immunosuppressive activity in cancers. In the ONO-4578-01 phase I study parts A/B, ONO-4578 (4578), which is an antagonist of EP4, alone and in combination with nivolumab (NIV) demonstrated a manageable safety profile in patients (pts) with advanced or metastatic solid tumors (Cancer Sci. 2023;114:211-220). Part C evaluated the safety, preliminary efficacy, and biomarkers of 4578 + NIV in pts with gastric or gastroesophageal (G/GEJ) cancer.

Methods

Part C was conducted at 22 sites in Japan, and it included pts with unresectable advanced or recurrent G/GEJ cancer who previously received at least two regimens. We categorized pts into three groups: IO-treated, pts who received immune-oncology (IO) treatment with anti-PD-(L)1 antibody as the most recent treatment; IO-naïve, pts without IO treatment; UGT1A1p, pts with UGT1A1 polymorphism. Pts received oral 4578 (40 mg) daily and NIV (480 mg) every 4 weeks. The primary endpoint was safety. We assessed biomarkers with multiple methods including immunostaining and RNA-seq using pts’ tumor tissues, and urine PGE₂ metabolite (PGEM) analysis.

Results

The IO-treated, IO-naïve, and UGT1A1p groups included 30, 30, and 6 pts, respectively, with a median age of 65.0 years. Treatment-related adverse events (TRAEs) occurred in 46 (70%) pts, wherein grade ≥3 TRAEs occurred in 17 (26%). No pts died due to TRAEs. Tolerability was confirmed in UGT1A1p. The investigator-assessed objective response and disease control rates were 10% and 73% in IO-treated and 17% and 40% in IO-naïve, respectively. Of note, >50% of the IO-treated pts achieved tumor shrinkage. In biomarker analyses, we observed signs of activated immune status in the tumor microenvironment after treatment, such as increases in T cell signature score and number, and relative increase of the ratio of M1 macrophage signature score to that of M2. Baseline urine PGEM, the potential surrogate marker of tumor PGE₂, was higher in pts with PR or SD than in pts with PD, suggesting the contribution of 4578 to the antitumor activity.

Conclusions

4578 + NIV demonstrated a manageable safety profile and antitumor activity in pts with G/GEJ cancer.

Clinical trial identification

NCT03155061.

Editorial acknowledgement

Drafting by Kumiko Yoshioka, PhD, of Ono Pharmaceutical.

Legal entity responsible for the study

The authors.

Funding

Ono Pharmaceutical Co., LTD.

Disclosure

H. Hirano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Teijin Pharma, Nichi-Iko, Novartis; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ono Pharmaceutical, Janssen Pharmaceutical, Merck Biopharma, Bristol Myers Squibb, Pfizer, Eisai, Amgen, Astellas, Seagen, MSD, Insyte, BeiGene, Novartis. A. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Expert Testimony: Merck & Co. K. Yamaguchi: Financial Interests, Personal, Invited Speaker: Taiho Pharm; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo, Bristol Myers Squibb, Ono Pharm, Eli Lilly Japan; Financial Interests, Institutional, Funding: Taiho Pharm. T. Hamaguchi: Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co., Ltd.; Other, Other, honorary: Ono Pharmaceutical Co., Ltd. Y. Narita: Financial Interests, Personal, Invited Speaker: Yakult, Taiho, Eli Lilly, Daiichi Sankyo, Ono, BMS; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Ono pharma, BMS, AstraZeneca, Daiichi Sankyo. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX Oncology. Y. Hamamoto: Financial Interests, Institutional, Invited Speaker: Ono Pharmaceutical Company. T. Esaki: Financial Interests, Personal, Invited Speaker: Chugai, Taiho, EP force, MSD, Daiichi Sankyo, Eli Lilly, Ono, Bristol; Financial Interests, Institutional, Research Grant: MSD, Novartis, Ono, Nihon Kayaku, IQVIA, Daiichi Sankyo, Chugai, Syneos Health Clinical, Pfizer, Dainippon Sumitomo, Quintiles, Eli Lilly, Parexel, Astellas, Astellas Amgen Biopharma, Eisai, Bayer, Asahikasei Pharma; Financial Interests, Institutional, Funding: Chugai, Nihon Kayaku. All other authors have declared no conflicts of interest.