Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

Abstract

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

Keywords: gastrointestinal cancer; immune checkpoint inhibitors; nivolumab; oesophageal cancer; pembrolizumab; programmed death receptor; stomach cancer.

Figure 1

Functional interaction of immune system and tumour cells in checkpoint inhibition (adapted from Taieb et al., 2018 [13].) Blocking checkpoint proteins, PD-1 (programmed death receptor-1), PD-L1 (programmed death receptor ligand-1), CTLA-4 (anti-cytotoxic T-lymphocyte-associated antigen 4), amplify T-cell immune response against tumour cells by blocking inhibitory signals of tumour cells. NK—natural killer, FcyR—Fc receptors for IgG, ADCC—antibody-dependent cellular cytotoxicity, MHC I/II—major histocompatibility complex, TCR—T-cell receptor.

Figure 2

Overview of curative therapy regimes of oesophageal and gastric cancer.

Figure 3

Overview of a possible algorithm for palliative therapy regimes in oesophageal cancer.

Figure 4

Overview of a possible algorithm for palliative therapy regimes in gastric cancer.