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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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
This work is licensed under a Creative Commons Attribution 4.0 International License .
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Supplementary data

Supplementary Methods S1

Supplementary Methods S1. PBMC analysis, Gene expression profiling, and Cytokines Measurement.

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Supplementary Figure S1

Supplementary Figure S1. Kaplan Meier plot for PFS and OS overall and stratified by presence/absence of liver metastases.

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Supplementary Figure S2

Supplementary Figure S2. PBMC subpopulation at baseline and at 2 months based on PFS duration or vorbipiprant dose.

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Supplementary Figure S3

Supplementary Figure S3. RNA-seq analysis of gene expression and pathways signatures.

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Supplementary Figure S4

Supplementary Figure S4. ESTIMATE-based deconvolution analysis comparing patients with PFS< or >4 months.

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Supplementary Figure S5

Supplementary Figure S5. Analysis of the DetermaIO immune related gene signature.

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Supplementary Table S1

Supplementary Table S1. Representativeness of Study Participants.

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Supplementary Table S2

Supplementary Table S2. Logistic regression analysis results of inflammatory gene expression signatures enrichment scores as predictors of treatment response.

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Supplementary Table S3

Supplementary Table S3. Results of Student's t-tests comparing enrichment scores of CIBERSORTx-based immune cell populations in patients with PFS< or >4months.

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Supplementary Table S4

Supplementary Table S4. Logistic regression analysis results of immunecell phenotypes enrichment scores as predictors of treatment response.

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