Research in context
Evidence before this study
We searched PubMed from inception until Jan 6, 2020, for clinical trials published in English assessing trastuzumab or pembrolizumab in oesophagogastric (or gastric, oesophageal, or gastro-oesophageal junction) cancer, using the search terms “trastuzumab” and “gastric cancer OR esophageal cancer,” then repeating the search by substituting “pembrolizumab” for “trastuzumab”. Following the results of the ToGA trial in 2010, trastuzumab plus fluoropyrimidine and platinum chemotherapy became the standard of care for HER2-positive metastatic oesophagogastric cancer. In the KEYNOTE-059 trial, pembrolizumab induced responses in patients with previously treated, PD-L1-positive metastatic oesophagogastric cancer. However, KEYNOTE-062 found no survival advantage for the combination of pembrolizumab and chemotherapy relative to first-line chemotherapy. To inform our investigation of molecular and genetic correlates of response, we also searched for predictors of response and resistance to trastuzumab by adding the term “biomarker” to the search. Resistance has been associated with activation of the receptor tyrosine kinase/KRAS and PI3K pathways, while greater response correlates with degree of HER2 (also known as ERBB2) amplification in tumour and circulating tumour DNA.
Added value of this study
To our knowledge, this is the first study to evaluate the synergistic potential of pembrolizumab, trastuzumab, and chemotherapy for previously untreated metastatic oesophagogastric cancer. We also explored potential molecular determinants of response to inform future studies to identify subsets of patients most likely to benefit from this combination.
Implications of all the available evidence
The results of this study suggest that the addition of pembrolizumab to trastuzumab and chemotherapy is safe and active in treating metastatic oesophagogastric cancer. The efficacy of this combination is being evaluated in the randomised double-blind phase 3 KEYNOTE 811 trial (NCT03615326).