Cancer Immunol Res. 2025 Nov 18. doi: 10.1158/2326-6066.CIR-25-0625. Online ahead of print.

ABSTRACT

The activity of bispecific antibodies against vascular endothelial growth factor (VEGF) and programmed death ligand-1 (PD-1) have reinvigorated interest in dual VEGF and PD-1 targeting across solid tumors. However, the tumor and immune features influencing tumor response remain largely unknown. We conducted a single arm phase II trial evaluating dual VEGFR2 and PD-1 targeting with ramucirumab and pembrolizumab in pre-treated PD-L1+ gastric cancer. Twenty-six patients were enrolled between June 2021 and May 2023. Nine patients received anti-PD-1 therapy before trial enrollment. There were no complete responses, but six patients had a partial response, for an objective response rate of 23%. Median progression-free survival was 2.7 months, and median overall survival was 10.9 months. Grade ≥3 treatment-related adverse events occurred in 39% of patients. Digital spatial profiling of serial primary tumor biopsies revealed distinct tumor microenvironment phenotypes between responders and non-responders. Responders were characterized by higher baseline tumoral VEGF signaling, baseline enrichment in antigen processing and presentation in the immune compartment, shorter distances between tumor and immune cell populations, and greater on-treatment vascular normalization coupled to cytotoxic T-cell infiltration. Non-responders had greater baseline hypoxia and PDGF scores, significantly upregulated TGF-β in immune cell regions, and greater distances between tumor and immune cells and immune cells and vessels. Paired peripheral blood mass cytometry revealed lower proportions of myeloid-derived suppressor cells in responders. Together these data highlight on-treatment remodeling under the therapeutic pressure of dual VEGF and PD-1 blockade, and suggest features associated with the durable benefit seen in a subset of patients.

PMID:41252599 | DOI:10.1158/2326-6066.CIR-25-0625