Sequential pembrolizumab cooperates with platinum/5FU to remodel the tumor immune microenvironment in advanced gastric cancer: A phase II sequential chemoimmunotherapy trial. Sequential chemoimmunotherapy in gastric cancer

The addition of anti-PD1 antibodies to frontline 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response, or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II clinical trial sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov: NCT04249739). Patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. Analysis of serial single-cell RNA sequencing (scRNAseq), whole exome (WES), whole transcriptome (WTS), and multiplex IHC (mIHC) defined broad and differential tumor immune microenvironment (TME) remodeling after chemotherapy and concurrent chemoimmunotherapy. Among 47 patients, early on-treatment induction of activated T-cell programs paralleled increases in anti-tumor macrophage subsets and radiographic response. Among responding patients there was further T-cell potentiation after anti-PD1 addition. Conversely, inability to induce immunogenic cell death modules was associated with suppressive macrophage populations and non-significant T-cell increases. These data suggest early TME remodeling informs the ability of concurrent PD-1 to provide additional anti-tumor benefit and suggests targeting tumor associated macrophage subsets warrants clinical evaluation to potentially expand the portion of GEA patients benefiting from immunomodulatory approaches.