Pembrolizumab in metastatic gastric cancer: comprehensive molecular characterization of clinical response

Programmed cell death 1 (PD-1) therapy is efficacious in a subset of patients with metastatic gastric cancer (mGC). We performed molecular characterization of tissues and cell-free tumor DNA (ctDNA) from 61 patients with mGC treated with pembrolizumab as salvage treatment. First, we demonstrated that MSI-H and EBV(+) tumors, which are mutually exclusive, responded to pembrolizumab dramatically (ORR 85.7% in MSI-H mGC and ORR 100% in EBV(+) mGC). For the 55 patients for whom PD-L1 CPS positivity was available (CPS cut-off value = 1%), ORR was significantly higher in PD-L1(+) GC when compared to PDL1(-) tumors. Changes in ctDNA levels at 6 weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular characteristics associated with pembrolizumab response in patients with mGC.