In patients with esophagogastric cancers undergoing immune checkpoint inhibitor treatment, testing for a mutation or deficiency in DNA MMR proteins is now mandatory. PD-L1 is the ligand that engages the programmed death receptor 1 (PD-1), leading to immune suppression in the tumor microenvironment. Key biomarkers emerging for immunotherapy in esophagogastric cancer include microsatellite instability (MSI) arising from DNA mismatch repair (MMR) protein deficiency, and programmed death ligand 1 (PD-L1) expression. With nearly all targeted therapies, including immunotherapy, not all patients benefit from new treatments, and biomarkers are used to select those most likely to benefit from these agents. This review covers recent practice-changing clinical trials that have advanced immunotherapy to the first-line treatment of esophagogastric cancer, and to the adjuvant setting in esophageal cancer.īiomarkers for the Selection of Immunotherapy
Recent advances, including the inclusion of trastuzumab in the first-line treatment of metastatic human epidermal growth factor receptor 2 (HER2)–positive disease 7 and the inclusion of ramucirumab (Cyramza, Lilly) in second-line treatment, 8 have now been surpassed by the advent of immune checkpoint inhibitor therapy. 2,6 Until recently, metastatic disease was treated with first-line chemotherapy consisting of a fluorinated pyrimidine and a platinum agent with or without a taxane, which achieved a median survival of less than 1 year. 3-5 The surgical management of esophageal cancer is combined with preoperative chemotherapy or chemoradiotherapy. The management of locally advanced gastric cancer consists of surgery combined with either perioperative chemotherapy, 2 the dominant practice in the West, or postoperative adjuvant chemotherapy, which is used more often in the East. In the United States and Western Europe, esophagogastric cancer is less common than in the high-incidence areas of East Asia, Eastern Europe, and South America. 1 When esophageal cancer is factored in, the case fatalities for esophagogastric cancer are second only to those for lung cancer. Gastric cancer is a leading type of cancer globally it is the fifth most common type of cancer and the fourth most common cause of cancer-related death. This article reviews recent advances in the use of immune checkpoint inhibitor therapy in esophagogastric cancers. In addition, the adjuvant use of nivolumab was recently approved in esophageal and GEJ cancer after chemoradiotherapy and surgery in patients with residual disease found at surgery. The addition of pembrolizumab to first-line chemotherapy in human epidermal growth factor receptor 2–positive esophagogastric adenocarcinoma was also recently approved. The addition of pembrolizumab to first-line chemotherapy in esophageal and GEJ adenocarcinoma and squamous cancer also improved all outcomes, which led to the approval of pembrolizumab as part of first-line chemotherapy. The addition of nivolumab to first-line chemotherapy in gastric and gastroesophageal junction (GEJ) adenocarcinoma improved survival, progression-free survival, and response, findings that led to regulatory approval. Pembrolizumab and nivolumab have received approval for the second-line treatment of esophageal squamous cancer. Initially approved for the treatment of chemotherapy-refractory programmed death ligand 1–positive or microsatellite instability (MSI)–high esophagogastric adenocarcinoma, these agents have been shown in earlier-line trials to have an additive benefit with first-line chemotherapy, and superiority to chemotherapy, in MSI-high cancers. Abstract: The uses of immune checkpoint inhibitors have now been advanced to include the first-line treatment of esophagogastric cancers.
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