Immunotherapy for Esophageal Cancer: State-of-the Art in 2021

SIMPLE SUMMARY: The aim of this review was to describe the rationale for immunotherapy in different stages of esophageal cancer (EC) treatment, with a particular accent on curative intent treatment of locally advanced disease for the two predominant histological types (adenocarcinoma and squamous cell cancer). In addition to the already existing literature on immunotherapy for advanced and metastatic stages of EC, the current study provides a comprehensive review of the leading ongoing trials in 2021 with a focus on earlier stages of treatment in neo adjuvant and adjuvant settings. ABSTRACT: The management of esophageal cancer (EC) has experienced manifold changes during the last decades. Centralization of EC treatment has been introduced in many countries, subsequently allowing the development of specialized high-volume centers. Minimal invasive surgery has replaced open surgery in many centers, whereas more potent systemic treatments have been introduced in clinical practice. Newer chemotherapy regimens increase long-term survival. Nevertheless, the overall survival of EC patients remains dismal for advanced tumor stages. In this direction, a wide range of targeted biologic agents (immunotherapy) is currently under assessment. Anti- Human Epidermal Growth Factor Receptor-2 (HER-2) monoclonal antibodies are used in HER2 (+) tumors, predominantly well-differentiated adenocarcinomas, and are currently assessed in the neoadjuvant setting (TRAP, INNOVATION trials). Immune checkpoint inhibitors Nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181), have demonstrated a survival benefit compared with conventional chemotherapy in heavily pre-treated progressive disease. More recently, CheckMate-577 showed very promising results for nivolumab in a curative adjuvant setting, improving disease-free survival mainly for esophageal squamous cell carcinoma. Several ongoing trials are investigating novel targeted agents in the preoperative setting of locally advanced EC. In addition, other immunomodulatory approaches such as peptide vaccines and tumor infiltrating lymphocytes (TILs) are currently under development and should be increasingly integrated into clinical practice.