Recent progress and current challenges of immunotherapy in advanced/metastatic esophagogastric adenocarcinoma.

The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in first-line therapy of programmed cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1 score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10) and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy plus pembrolizumab has beneficial response rates and resulted in approval in the USA (KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance to immunotherapy or the role of gender in response to ICI need to be clarified. This review provides an overview of the current approvals of ICI in advanced EGAC and reflects results of relevant phase II/III trials with focus on possible biomarkers, including PD-L1 CPS and microsatellite-instability (MSI) status.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.M. advisory roles for BMS, MSD, Merck, Amgen, BeiGene, Novartis, Lilly, Macrogenics, Roche, Sanofi, Servier, and Taiho. A.H. was a member of the advisory board of BMS. A.D. Wagner: Consultant or advisory role: Merck, Lilly, Pierre Fabre Pharma, Sanofi, Daichii Sankyo, Dragon-Fly Therapeutics, Servier, BMS, Astellas. I am coordinating investigator of EORTC-TRIAL 1203, which is supported by an educational grant from Roche to EORTC. R.O.: reports personal fees from BMS, Servier, Merck, Merck KGaA and a research grant from Roche (institutional). M.A.: Maria Alsina reports financial interest in form of scientific consultancy role for Amgen, BMS, MSD, Lilly and Servier. P.T-P.: Honoraria for advisory role: Astellas, BMS, Lilly, Merck, MSD, Nordic, Pfizer, Roche, Teva, Research Grants: Merck, GSK, Novartis. H.v.L: Consultant or advisory role: BMS, Dragonfly, Lilly, Merck, Nordic Pharma, Servier. Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier.
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