Distinct Spatially Resolved Tumor Microenvironment Trajectories Define Benefit from Ramucirumab plus Pembrolizumab in Refractory PD-L1+ Gastric Cancer.

The activities of bispecific antibodies against VEGF and 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 pretreated 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%. The median progression-free survival was 2.7 months, and the 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 nonresponders. 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. Nonresponders had greater baseline hypoxia and platelet-derived growth factor scores, significantly upregulated TGFβ 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.