Phase I/II study of the EP4 antagonist vorbipiprant combined with anti-PD-1 immunotherapy: Safety and efficacy results in metastatic gastrointestinal non-colorectal cancers.

2608 Background: Novel combination strategies are being explored to enhance the effectiveness of immune checkpoint inhibitors (ICIs). Prostaglandin E2, through its receptor 4 (EP4), is a major contributor to immunosuppression in the tumor microenvironment. In a dose-response phase I/II study, the EP4 antagonist vorbipiprant (CR6086) combined with PD-1 blockade was well tolerated and showed promising efficacy in refractory mismatch-repair-proficient/microsatellite stable metastatic colorectal cancer (CRC) (Pietrantonio et al, Clin Cancer Res 2024). Here we report the results from a study extension in non-colorectal gastrointestinal (GI) cancers with the vorbipiprant dose selected for further development in combination with immunotherapy. Methods: Twenty-seven adult patients (pts) with metastatic non-colorectal GI cancers, ECOG PS ≤1, and ≥1 prior treatment line were included in 3 cohorts (9 pts each): gastric cancer (GC) with PD-L1 Combined Positive Score (CPS) ≥5 (cohort A), GC with PD-L1 CPS < 5 (cohort B), and GI cancers other than CRC and GC (cohort C). Pts receive oral vorbipiprant (90 mg twice daily) plus iv balstilimab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity or death. Primary endpoints are safety and disease control rate (DCR) per RECIST 1.1. Secondary endpoints include objective response rate, progression-free and overall survival (ORR, PFS, OS). Exploratory endpoints include tissue and blood biomarkers. Results: At a cutoff date of November 20, 2024, enrolment is completed. In cohort C, we enrolled: 5 BTC, 2 pancreatic and 2 ampullary cancer patients. Overall, median age was 61 (interquartile range: 55-68) years, similar among cohorts; 70% were men, with a slightly higher prevalence in Cohort A; the median number of prior treatment lines was 3 (IQR: 2-4) overall and in gastric cohorts, and 2 (IQR: 2-3) in other GI cancers cohort. Prior ICIs were administered in 44%, 22% and 11% in Cohort A, B and C, respectively. No treatment-related serious or grade > 3 adverse events were reported. Promising activity was observed. In cohort A, 3 pts had a partial response (PR), 2 of them still ongoing and 2 lasting more than 6 months; in addition, 1 pt had stable disease (SD). In cohort B, 4 pts had SD, 1 of them still ongoing and 2 lasting more than 6 months. In cohort C, 1 pt with pancreatic cancer had a PR, still ongoing for > 6 months; in addition, 1 BTC patient had SD. Median PFS and OS were: 4,5 and 9,7 months in Cohort A, 1,8 and 6,8 months in Cohort B, 2,0 and 4,5 months in Cohort C. Responses occurred irrespective of MSI/MMR status and prior exposure to ICIs. Conclusions: Vorbipiprant combined with PD-1 blockade was well tolerated and showed signs of activity in non-colorectal GI cancers, thus confirming a broader spectrum of activity on top of the results in MSS CRC. Clinical trial information: NCT05205330 .