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Immune Checkpoint Inhibition in Esophagogastric Cancers

Tomas G. Lyons, MD, and Geoffrey Y. Ku, MD
Published Online: Dec 29,2017

Geoffrey Ku, MD
Abstract

The poor prognosis for patients with esophagogastric cancers (EGC) requires the development of newer more effective therapies to further improve the treatment outcomes for this disease. Immunotherapy is a novel treatment strategy that is dramatically changing the treatment landscape for several types of cancers. Cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody and antagonists of the programmed death (PD)-1/PD-ligand 1 are essential immune checkpoint inhibitors that suppress T-cell activation. Targeting of these immune checkpoints with monoclonal antibodies has shown clinical efficacy in several solid tumors which has led to their approval and use in routine clinical practice. In EGC early phase evaluation of immune checkpoint inhibitors has yielded encouraging results with multiple phase III studies currently ongoing. In this review, the biological rationale for the use of immune checkpoint inhibitors in cancer will briefly be described and the accumulating data concerning their use in EGC will be presented.

Introduction

In the United States, esophagogastric cancers (EGCs) are an uncommon but aggressive disease. In 2016, an estimated 26,370 patients were diagnosed with gastric cancer, with an estimated 10,370 deaths. Esophageal cancer cases will number 16,940, with an estimated 15,690 deaths during the same time period.1 Approximately 50% of patients diagnosed with EGC present with overt metastatic disease and chemotherapy is the mainstay of palliation in this setting. The majority of patients will develop chemotherapy resistance, and treatment options beyond first or second line are limited in this disease. With the exception of trastuzumab with first-line chemotherapy for HER2-positive disease2 and ramucirumab as monotherapy3 or with paclitaxel chemotherapy4 in the second-line setting, results of clinical trials utilizing targeted agents have not resulted in efficacious therapeutic options for patients.

Recent years have seen the treatment landscape for many cancers changed dramatically with the development of immune-directed therapies, specifically immune checkpoint inhibitors. There has been growing excitement among oncologists and patients alike for the use of checkpoint inhibition in EGC. The first checkpoint inhibitor drug to be approved by the FDA in 2011 was the anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in advanced melanoma.5,6 Since then, antagonists of the programmed death (PD)-1/PD-ligand 1 pathway have undergo extensive evaluation in multiple other solid tumors, with FDA approval of  immune checkpoint inhibitors in melanoma, non–small cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, squamous cell carcinoma of the head and neck, Merkel cell carcinoma, and Hodgkin lymphoma. In EGC, early-phase evaluation of immune checkpoint inhibitors has yielded encouraging results, culminating in ongoing phase III studies. Pembrolizumab which is an anti-PD-1 inhibitor was approved by the FDA in September 2017 for PD-L1–positive gastric cancer patients who have received 2 or more lines of therapy in the advanced setting. This accelerated approval was based on results of a phase II study and is contingent on results of a confirmatory trial.   In this review, the biological rationale for the use of immune checkpoint inhibitors in cancer will briefly be described and the accumulating data concerning their use in EGC will be presented.



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Immune Checkpoint Inhibition in Esophagogastric Cancers
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