Pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction cancer: an evidence-based review of place in therapy

Gastric and esopahgeal cancers account for the six most common causes of cancer death worldwide. Locally advanced resectable cancers have a 5-year life expectancy of 30%. Despite use of chemotherapy, median overall survival for stage IV cancer rarely exceeds 1 year. A subset of gastric cancers such as microsatellite-instable tumor and Epstein-Barr virus-positive tumors have a rich immune infiltrate that makes them more responsive to immune-directed therapies. Tumors can evade T-cell-mediated "immune surveillance" by activating the programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway. Targeting PD-1 and thus de-engaging them from its ligands can help restore immunogenicity. Pembrolizumab is the first immunotherapy to be approved by US FDA for PD-L1 expressing gastric and gastroesopahgeal junction (GEJ) cancers after they have progressed on at least two prior lines of treatment. While PD-L1 positivity does not define tumor's responsiveness to pembrolizumab, PD-L1-positive tumors have better overall response rates. The treatment is usually well tolerated and has a favorable adverse events profile. The exact setting for use of pembrolizumab remains to be determined. Pembrolizumab failed to improve overall survival when administered as second-line treatment for advanced, metastatic gastric and GEJ cancers. There are several ongoing studies with various combinations and different settings not only with pembrolizumab but also with other checkpoint inhibitors.