3560 Background: Novel combination strategies are being explored to enhance the effectiveness of immune checkpoint inhibitors (ICIs) in pMMR/MSS mCRC. Prostaglandin E2, through its receptor 4 (EP4), is a major contributor to immunosuppression in the tumor microenvironment and blockade of this pathway may sensitize cold tumors to ICIs. Vorbipiprant (CR6086) is a potent and selective EP4 antagonist that significantly enhanced the activity of PD-1 blockade in MSS preclinical models. Preliminary analysis of a phase I/II clinical trial of vorbipiprant added to the anti-PD-1 balstilimab in pMMR/MSS chemorefractory mCRC showed promising efficacy and acceptable safety of the recommended doses of this combination. Here we report updated results and subgroup analyses of efficacy outcomes including by presence of liver metastases (LM) (data cutoff January 8, 2024). Methods: Adult patients (pts) with pMMR/MSS mCRC, ECOG PS ≤1 and previous exposure to fluoropyrimidines, oxaliplatin and irinotecan, received oral vorbipiprant (30, 90 or 180 mg twice daily) plus balstilimab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity or death. Primary endpoints were safety and disease control rate (DCR) per RECIST 1.1. Secondary endpoints included objective response rate (ORR), duration of response, progression-free and overall survival (PFS, OS). Ongoing exploratory endpoints include tissue and blood biomarkers. Results: Twenty-eight pts were treated. Median age was 59 (interquartile range [IQR]: 54-68) years, 54% were men and median prior treatment lines was 4 (IQR: 3-5). Twelve pts (43%) had LM at enrollment. Overall, 3 pts had partial response and 11 had stable disease, leading to an ORR of 10.7% and a DCR of 50%. At a median follow-up of 12.5 months (IQR 8.9-14.7 months), median PFS was 2.6 months (95% CI 1.7-3.6 months), and median OS was 13.7 months (95% CI 10.6-not reached). In pts with LM, ORR was 8% and DCR was 25%; 1 pt had a durable ongoing response exceeding 20 months and the treatment is still ongoing; median PFS was 1.8 months (95% CI 1.6-3.5 months), and median OS was 13.7 months (95% CI 5.5-not reached). In pts without LM, ORR was 12.5% and DCR was 68.8%; median PFS was 3.6 months (95% CI 1.8-7.2 months), and median OS was not reached (95% CI 10.6-not reached). Translational analyses are ongoing to elucidate immune infiltration patterns behind the clinical benefits seen also in pts with LM. Conclusions: Vorbipiprant combined with an anti-PD-1 (balstilimab) showed promising efficacy in this phase I/II study. Encouraging results were observed in pts with LM. This finding deserves particular attention given that the presence of LM is considered an immune resistance factor and is associated with poor outcomes of treatment with ICIs. Clinical trial information: NCT05205330 .