A phase 2 trial of peri-operative avelumab and chemotherapy for locally advanced gastro-esophageal adenocarcinoma: Association of AGR2/AP-1 complex CD8 T-cells and M2-Tumour Associated Macrophages with treatment response

Abstract

Perioperative chemo-immunotherapy represents a promising treatment modality for locally advanced gastroesophageal adenocarcinoma (GEA). However, the potential of these novel treatments has yet to be realized and efforts to identify patients who would benefit for targeted therapies have been unsuccessful. Herein we present the clinical results of a phase 2 trial combining neoadjuvant docetaxel, cisplatin, 5FU and the PD-L1 inhibitor avelumab for patients with locally advanced GEA and describe the tumor inflammatory microenvironment associated with response. Fifty-one patients were enrolled and received neoadjuvant therapy with 50 proceeding to surgery. Grade 3-4 adverse events occurred in 40% of patients. Major pathological response occurred in 9/50 patients (18%). No correlation was found between tumor regression and PD-L1, MMR protein expression or reduction in standard uptake values on PET. Multiplex immunohistochemistry revealed CD8+ T cell proliferation in post-operative specimens, particularly among individuals who responded well to the treatment, and a greater predominance of M2-Tumour Associated Macrophages in poor-responders. Single cell transcriptomic profiling of treatment naïve tumors also indicated differential gene expression among T cells, and in particular higher differences in CD8+ central memory T cells in responders when compared to non-responders to neoadjuvant therapy. We found the expression of AGR2 of genes belonging to the activator protein-1 (AP-1) complex, such as JUND, was closely associated with pathological response. This finding provides evidence of novel predictors of response to neoadjuvant chemo-immunotherapy and identifies potential direction to personalize neoadjuvant therapy with a view to improving treatment response. Trial registration information: The study is registered on www.clinicaltrials.gov URL: https://clinicaltrials.gov/ct2/show/NCT03288350 (NCT03288350)