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Clinical Trial
. 2025 Feb 17;31(4):649-658.
doi: 10.1158/1078-0432.CCR-24-2611.

The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite-Stable Metastatic Colorectal Cancer: A Phase Ib/IIa Trial

Filippo Pietrantonio  1 , Federica Morano  1 , Monica Niger  1 , Filippo Ghelardi  1 , Claudia Chiodoni  2 , Michele Palazzo  1 , Federico Nichetti  1   3 , Paolo Manca  1   4 , Eleonora Cristarella  1 , Valentina Doldi  5 , Nadia Zaffaroni  5 , Giovanna Sabella  6 , Nadia Brambilla  7 , Elena Benincasa  7 , Giampaolo Giacovelli  7 , Cristina Vitalini  7 , Federica Girolami  7 , Lucio C Rovati  7   8
Affiliations
Clinical Trial

The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite-Stable Metastatic Colorectal Cancer: A Phase Ib/IIa Trial

Filippo Pietrantonio et al. Clin Cancer Res. .

Abstract

Purpose: Novel combinations are required to overcome resistance to immune checkpoint inhibitors in proficient mismatch repair (pMMR) or microsatellite-stable (MSS) metastatic colorectal cancer (mCRC). We aimed to determine whether vorbipiprant, a prostaglandin E2 receptor EP4 subtype antagonist, can convert immune-resistant mCRC into a tumor responsive to anti-PD-1 inhibition.

Patients and methods: This phase Ib/IIa prospective, open-label, single-arm trial followed a 3 + 3 dose-escalation and dose-optimization design. A total of 28 patients with chemorefractory pMMR/MSS mCRC were given dose-escalated oral vorbipiprant (30, 90, or 180 mg twice daily), along with biweekly intravenous balstilimab (3 mg/kg), an anti-PD-1 antibody. The primary endpoints included safety and the disease control rate (DCR). Secondary endpoints were the overall response rate, duration of response, progression-free survival, and overall survival.

Results: No dose-limiting toxicities were observed. Of the 28 patients, seven (25%) experienced serious adverse events, but only one was attributed to vorbipiprant and one to balstilimab. The trial achieved a DCR of 50% observed across the entire cohort. In the subgroup of patients with liver metastases (n = 12), the DCR was 25%. The overall response rate was 11%, with three patients showing a partial response (median duration of response, 7.4 months). The median progression-free survival was 2.6 months, and the median overall survival was 14.2 months. Translational exploratory analyses suggested that vorbipiprant may boost response to anti-PD-1 in patients with immunogenic tumors.

Conclusions: The combination of vorbipiprant and a PD-1 inhibitor (balstilimab) yielded sufficient activity in refractory pMMR/MSS mCRC, which is worthy of confirmation in future clinical trials in biomarker-enriched populations.

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Conflict of interest statement

F. Pietrantonio reports grants from Eli Lilly and Company, Bristol Myers Squibb, Incyte, AstraZeneca, Amgen, and Agenus; personal honoraria as an invited speaker from BeiGene, Daiichi Sankyo, Seagen, Astellas, Ipsen, AstraZeneca, Servier, Bayer, Takeda, Johnson & Johnson, Bristol Myers Squibb, MSD, Amgen, Merck Serono, and Pierre Fabre; and advisory/consultancy honoraria from Bristol Myers Squibb, MSD, Amgen, Pierre Fabre, Johnson & Johnson, Servier, Bayer, Takeda, Astellas, GSK, Daiichi Sankyo, Pfizer, BeiGene, Jazz Pharmaceuticals, Incyte, Rottapharm Biotech, and Merck Serono during the conduct of the study. F. Morano reports personal fees from Pierre Fabre and Servier; nonfinancial support from Pierre Fabre, Amgen, and AstraZeneca; and grants from Incyte outside the submitted work. M. Niger reports personal fees from Incyte, MSD Italia, Servier, Taiho, Basilea Pharmaceutica, Sandoz, Med Point s.r.l., and Accademia della Medicina and personal fees and other support from AstraZeneca outside the submitted work. F. Nichetti reports personal fees from AstraZeneca outside the submitted work. E. Benincasa reports other support from Rottapharm Biotech during the conduct of the study, as well as other support from Bicara Therapeutics outside the submitted work. L.C. Rovati reports a patent for WO2013004290 issued and a patent for WO2020208088 issued. For the sake of clarity, L.C. Rovati and other authors (N. Brambilla, E. Benincasa, G. Giacovelli, C. Vitalini, F. Girolami) report employment with Rottapharm Biotech, the company who sponsored the study, as cited in the Conflict of Interest Disclosure in the manuscript. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Trial profile and clinical response. Trial profile showing the number of patients screened, the patients enrolled, and, finally, the number of patients discontinued by the treatment groups (A). Swimmer plot showing the duration of treatment with vorbipiprant and balstilimab and RECIST overall tumor assessments (B). LM, liver metastases; PD, progressive disease. Spider plot showing the tumor burden over time presented as percentage change in the sum of the target lesions (C). Waterfall plot reporting treatment response according to PD-L1 CPS (D). NA, not assessable. Vorbipiprant dose always combined with the PD-1 inhibitor balstilimab, if not indicated.
Figure 2.
Figure 2.
Gene expression signatures, immune cell enrichment and gene expression–based CMS, and association with treatment response. Treeplot depicting the results of hierarchical clustering of enriched terms from GSEA, comparing enriched pathways in patients with PFS <4 or >4 months (A). Bar plot reporting the results of the Student t test t statistics comparing inflammatory gene expression signature enrichment scores in patients with PFS >4 months vs. those with PFS <4 months (B). Heatmap of normalized enrichment scores of immune cell subtypes, comparing patients with PFS <4 or >4 months (C). DC, dendritic cells; iDC, immature dendritic cells; mDC, mature dendritic cells; MDSC, myeloid-derived suppressor cells; pDC, plasmacytoid dendritic cells; TFG, follicular helper T cells; TGD, gamma-delta T cells; Treg, regulatory T cells. Stacked barplots representing the proportion of patients assigned to gene expression CMS in patients with PFS >4 months (n = 6) and patients with PFS <4 months (n = 17; D).
See this image and copyright information in PMC

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