Abstract 55P
Background
The phase I study, ONO-4578-01, demonstrated antitumor activities of ONO-4578 (4578), an EP4 antagonist, plus nivolumab (NIV) in solid tumors (ESMO, 2023; ASCO-GI, 2024). This ONO-4578-02, open-label, phase 1 study assessed the safety, preliminary efficacy, and biomarkers of 4578 in combination with NIV and chemotherapy (Chemo) in treatment-naive pMMR/MSS mCRC.
Methods
Patients received 4578 (40 mg) daily and NIV (360 mg) every 3 weeks in addition to chemo (capecitabine, oxaliplatin, bevacizumab). The primary endpoints were tolerability and safety. Preliminary efficacy and biomarkers (through immunostaining and RNA-seq) were also assessed.
Results
A total of 34 patients received the treatment: 30 (88.2%) with an ECOG PS of 0, 26 (76.5%) with primary tumor on the left side, 26 (76.5%) with liver metastases, and 13 (38.2%) with wild-type RAS. The median age was 66 years. The PD-L1 combined positive score (CPS) was ≥1 and <1 in 17 and 14 patients, respectively. Treatment-emergent adverse events (TEAEs) occurred in 34 (100%), including 28 (82.4%) with grade ≥3 and 20 (58.8%) with serious TEAEs; 15 patients (44.1%) discontinued of any study treatment due to TEAEs. No patient died due to TEAEs. The results confirmed the tolerability of 4578 (40 mg) combined with NIV and Chemo. The objective response rate (ORR) was 73.5% (partial response, 25 patients) and the median progression-free survival (PFS) was 12.3 months (95% CI, 7.0–17.1). Of note, favorable ORR and PFS were observed in patients with a CPS of ≥1 vs <1 (ORR, 88.2% vs 64.3%; median PFS, 12.3 vs 7.4 months). The biomarker analyses revealed that patients with a CPS of ≥1 had a greater number of CD8+ T cells in tumor tissues at baseline compared to those with a CPS of <1. Additionally, an increased number of CD8+ cells and the signs of activated T cells and M1/M2 macrophages were observed in tumor tissues after treatment.
Conclusions
The combination of 4578 with NIV and Chemo demonstrated a manageable safety profile in patients with pMMR/MSS mCRC, along with promising antitumor activities, particularly in those with a CPS of ≥1.
Clinical trial identification
ONO-4578-02 (jRCT2031200215).
Legal entity responsible for the study
Ono Pharmaceutical Co., Ltd.
Funding
Ono Pharmaceutical Co., Ltd.
Disclosure
Y. Kagawa: Financial Interests, Personal, Invited Speaker: Bayer, Chugai, Ono, Lilly, Merck, Takeda, MSD; Financial Interests, Personal and Institutional, Invited Speaker: Ono. T. Kato: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Eli Lilly and Company, Ono Pharmaceutical Co, Takeda Pharmaceutical Company Limited, Asahi Kasei; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co. M. Shiozawa: Financial Interests, Personal, Invited Speaker: Lilly Japan, Merck Serono, Taiho Pharmaceutical, Yakult Honsha, Takeda, Ono Pharmaceutical, Johnson & Johnson, Kaken. K. Yamaguchi: Financial Interests, Personal, Invited Speaker: Taiho Pharm; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo, Bristol Mayers Squibb, Ono Pharm, Eli Lilly Japan; Financial Interests, Institutional, Funding: Taiho Pharm. M. Gotoh: Financial Interests, Personal, Invited Speaker, speaker: Ono Pharmaceutical Co., Ltd., MSD K.K.; Financial Interests, Institutional, Funding: Chugai Pharma, Taiho Pharmaceutical, Nippon Kayaku. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin; Financial Interests, Institutional, Invited Speaker: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen. T. Hamaguchi: Financial Interests, Institutional, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Other, honorary: Ono Pharmaceutical Co., Ltd. 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. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd., Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., Falco Biosystems Ltd.