Esophageal, gastric cancer and immunotherapy: small steps in the right direction?

Adam Zayac, Khaldoun Almhanna


The treatment of advanced, solid-tumor oncology has been reshaped over the last eight years with the development and FDA approval of several immune checkpoint inhibitors (ICIs) comprised of monoclonal antibodies targeting either PD-1, PD-L1, or CTLA-4 across numerous disease states and indications. Yet, despite their vast expansion of use in both solid-tumor and hematologic malignancies, gastrointestinal cancers have had limited approvals to date. This review article will focus on the use of the currently studied, approved uses and the potential future roles of ICIs in the treatment of cancers of the upper gastrointestinal tract through recent updates on ongoing studies and discussion of phase III studies underway. A single immunotherapy agent, Pembrolizumab, is the only currently approved treatment option in subset of patients with unresectable locally advanced, recurrent, or metastatic esophageal, gastroesophageal, or gastric cancers after failure or intolerance of initial systemic treatments. The only patients who are currently considered for treatment with ICI are those with tumors that are either microsatellite instability-high (MSI-H), DNA mismatch repair deficient (dMMR), or in those with esophageal, GEJ, or gastric adenocarcinomas that have at least one-percent expression of PD-L1 after failing at least two lines of systemic therapy based on early results from the KEYNOTE-059 trial released in 2017, or second-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) with combined positive score (CPS) of 10 or greater based on the combined results from KEYNOTE-180 and KEYNOTE-181 in 2019. However, despite these limited successes thus far, there are numerous ongoing studies evaluating several ICIs for efficacy and safety in esophageal, GEJ, and gastric cancers. These agents are being studied in countless aspects of these malignancies: from neoadjuvant and adjuvant treatment in resectable disease to first-line treatment and beyond in the advanced, unresectable, or metastatic setting. In this article we will review the currently approved agents as well as ongoing clinical trials that will be approaching completion in the next 5 years, potentially altering the landscape of treatment in upper GI malignancies.