Combining chemotherapy, trastuzumab, and immune-checkpoint inhibitors in HER2-positive gastro-oesophageal cancer

HER2 overexpression or amplification occurs in 17–23% of gastro-oesophageal-adenocarcinoma tumours, driving oncogenesis. 1 Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014; 513: 202-209 Crossref PubMed Scopus (4360) Google Scholar , 2 Van Cutsem E Bang YJ Feng-Yi F et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015; 18: 476-484 Crossref PubMed Scopus (376) Google Scholar The ToGA trial showed a survival advantage for trastuzumab, an anti-HER2 monoclonal antibody, with cytotoxic chemotherapy in HER2-positive (ie, IHC3-positive or IHC2-positive and fluorescence in situ hybridisation [FISH]-positive) advanced gastro-oesophageal adenocarcinoma. 3 Bang YJ Van Cutsem E Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376: 687-697 Summary Full Text Full Text PDF PubMed Scopus (5612) Google Scholar Immune-checkpoint inhibition via anti-PD-1 antibodies and chemotherapy has improved survival in advanced, untreated gastro-oesophageal adenocarcinoma. The survival benefit from anti-PD-1 therapy is primarily confined to patients exhibiting tumour expression of PD-L1. 4 Lordick F Carneiro F Cascinu S et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022; 33: 1005-1020 Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar A majority of HER2-positive gastro-oesophageal-adenocarcinoma tumours co-express PD-L1, and preclinical models suggest synergy in dually targeting HER2 and PD-L1 axes. 5 Janjigian YY Kawazoe A Yañez P et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021; 600: 727-730 Crossref PubMed Scopus (261) Google Scholar Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trialCompared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis. Full-Text PDF