Distinct microenvironment phenotypes across tumor, vascular, and immune compartments from ramucirumab plus pembrolizumab in refractory gastric cancer: A phase II trial.

4034 Background: Combining immune checkpoint inhibitor (ICI) with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. This phase II trial investigated the efficacy and molecular mechanisms of ramucirumab plus pembrolizumab in refractory gastric cancer patients. Methods: We conducted a prospective phase II single-arm trial of ramucirumab plus pembrolizumab as salvage treatment in patients with metastatic GC who failed to respond to standard fluoropyrimidine plus platinum with or without programmed cell death protein 1 (PD-1) inhibitors. Eligible patients had programmed death-ligand 1 (PD-L1) combined positive score more than five. The primary objective was to objective response rate (ORR) and secondary end points included disease control rate, duration of response, progression-free survival and overall survival, and toxicity. Comprehensive molecular profiling, including Digital Spatial Profiling, and mass cytometry was performed on tumor samples and peripheral blood. Results: Twenty-six patients were enrolled in this study between June 2021 and May 2023. No patient attained complete response (CR), while 6 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 23.1% (95% CI, 4.06–34.4). The median PFS for all patients was 2.7 months (95% CI, 1.84 - 3.56 months), and median OS was 10.9 months (95% CI, 2.31 – 18.29). Grade ≥ 3 treatment-related adverse events occurred in 38.5 % of patients. Digital Spatial Profiling revealed distinct tumor microenvironment (TME) phenotypes between responders and non-responders. Responders had high CTL infiltration and vascular normalization in their tumor specimen after treatment which led to favorable treatment outcome. In support of this, spatial profiling revealed the shortest median distance between immune cells and vessels, suggesting enhanced transendothelial migration of immune cells. Nonresponders had significantly upregulated TGF-β pathway and low tumor vascularity. On-treatment analysis demonstrated a shift towards increased immune cell infiltration and decreased tumor cellularity. Mass cytometry of peripheral blood revealed lower proportions of myeloid-derived suppressor cells in responders. Conclusions: Ramucirumab+pembrolizumab showed modest clinical efficacy, with manageable toxicity and durable responses. Although limited to a small subset of patients, a few patients who had previously responded to ICI benefited from ramucirumab+pembrolizumab. Clinical trial information: NCT0005753 .