The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Phase 1b/2a Trial

Abstract

Purpose: Novel combinations are required to overcome resistance to immune checkpoint inhibitors (ICIs) in proficient mismatch repair (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC). We aimed to determine whether vorbipiprant, a prostaglandin EP4 receptor antagonist, can convert immune-resistant mCRC into a tumor responsive to anti-PD-1 inhibition. Patients and Methods: This phase 1b/2a 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 objective response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS). Results: No dose-limiting toxicities were observed. Out 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) DCR was 25%. The ORR was 11%, with three patients showing a partial response (median duration of response: 7.4 months). Median PFS was 2.6 months and median OS 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, worth of confirmation in future clinical trials in biomarker-enriched populations.