Tumor microenvironment evaluation to predict pembrolizumab benefit of metastatic gastric cancer: Results from phase II clinical trial.

Abstract

425 Background: Clinical studies support the efficacy of immune checkpoint blockades (ICBs) in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response to ICBs, we performed molecular characterization of tissues from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial (NCT#02589496). Methods: Of 61 patients, 60 patients underwent pretreatment biopsy and 45 specimens were of sufficiently high quality for RNA sequencing. TMEscore, which was previously established to quantify the tumor microenvironment (TME), was used to estimated TME of pretreatment specimens. The predictive value and correlation of integrative molecular characterization were systematically explored. Results: We established a methodology (TMEscore) to evaluated the TME of GC patients, which was previously found to be a robust prognostic and predictive biomarker for patients treated with ICBs. By applying ROC curve analysis, the TMEscore was found to be a best predictive biomarker (TMEscore: AUC = 0.891; CPS: AUC = 0.830; TMB: AUC = 0.672; MSI status: AUC = 0.708; EBV status: AUC = 0.727; respectively). Moreover, TMEscore was the most significant gene signature that correlated with tumor response (TMEscore: P = 1.7 × 10 −5; GEPs: P = 0.00035; ImmunoScore: P = 0.29106; CD8+ T cell fraction: P = 0.00011; Immune checkpoint score: P = 0.00149; respectively). TMB was not correlated with TMEscore (Kruskal-Wallis test, P = 0.14). A higher TMEscore was significantly associated with EBV+ and high-MSI TCGA molecular subtypes (Kruskal-Wallis test, P = 0.002) which were reported to benefit from ICBs of GC. Conclusions: These findings indicate that the assessment of TMEscore via high throughput-sequencing and PCA algorithm provides a robust biomarker for the selection of GC patients who may derive greater benefit from pembrolizumab. Our data also suggest that TMEscore may be a more accurate predictive biomarker than TMB, MSI and EBV status, and this resource may help facilitate the development of precision immunotherapy. Clinical trial information: NCT#02589496.