Safety and Efficacy of Pembrolizumab in Combination With FLOT About Gastroesophageal Junction Cancer:

Overview

At present, surgery is still the main treatment for gastroesophageal junction cancer. At the same time, multimodal comprehensive treatment such as chemotherapy and molecular targeted therapy can effectively alleviate pathological progression, facilitate R0 resection and improve the overall survival of patients.Pembrolizumab, as a PD-1 inhibitor, has been shown to have antitumor activity and a manageable safety profile in gastroesophageal junction cancer.Pembrolizumab combined with chemotherapy has become a research hotspot. However, to date, there is no clinical study related to gastroesophageal junction cancer. In this study, Pembrolizumab combined with FLOT was used as the first-line treatment for gastroesophageal junction cancer, aiming to explore the experience chemotherapy mode for gastroesophageal junction cancer.

Gastric cancer, including gastroesophageal junction cancer, is the fifth most common cancer and the third leading cause of death in the world. Among them, although the incidence of distal gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction cancer is increasing. At present, surgery is still the main treatment for gastroesophageal junction cancer. At the same time, multi-mode comprehensive treatment such as chemotherapy and molecular targeted therapy can effectively alleviate pathological progression, facilitate R0 resection and improve the overall survival of patients. A large number of previous clinical trials on the combination of first-line chemotherapy and molecular targeted drugs in the treatment of gastric and gastroesophageal junction cancer have shown that only trastuzumab can improve the overall survival rate of Her-2 positive patients. In addition, despite various clinical chemotherapy regimens, the median survival time of gastric cancer and gastroesophageal junction cancer is not high. Therefore, the treatment mode of gastroesophageal junction cancer, especially for Her-2 negative patients, needs to be explored and improved. In recent years, immune checkpoint inhibitors represented by programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1) inhibitors have been applied to the treatment of a variety of solid tumors such as melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and urothelial cancer. It has become another important treatment strategy after surgery, chemotherapy, radiotherapy and targeted therapy. Studies have shown that PD-L1 is highly expressed in tumor cells and immune cells in gastric cancer and gastroesophageal junction cancer and plays a key role in tumor immune escape, therefore, the PD-1/ PD-L1 pathway will become an important target for effective intervention in gastroesophageal junction cancer. As a PD-1 inhibitor, Pembrolizumab has been shown to have anti-tumor activity and manageable safety in gastroesophageal junction cancer, and was approved by the US FDA in September 2017 for advanced PD-L1-positive gastric or gastroesophageal junction cancer . The phase Ⅱ KEYNOTE-059 trial used Pembrolizumab as a single agent in the third-line treatment of advanced gastric or gastroesophageal junction cancer, and the results showed that it had controllable safety in patients with PD-L1 positive, with obvious advantages in objective response rate (ORR) and median duration of response (DOR) \[12\]. Chemotherapy enhances tumor immune responses by enhancing tumor cell immunogenicity and sensitivity to immune killing, and the combination of chemotherapy and immune checkpoint inhibitors has been shown to improve overall survival in several cancer types. Therefore, PD-1/ PD-L1 immunosuppressant combined with chemotherapy has become a hot spot in the research of advanced gastric cancer or gastroesophageal junction cancer . The phase 3 KEYNOTE-062 trial compared Pembrolizumab plus chemotherapy (cisplatin plus 5-FU or capecitabine) with chemotherapy alone or Pembrolizumab alone in the first-line treatment of advanced gastric or gastroesophageal junction cancer. However, compared with chemotherapy alone, Pembrolizumab combined with chemotherapy could not significantly prolong the overall survival of patients, and the overall effect was not better than chemotherapy alone . In contrast, the phase III KEYNOTE-590 study, designed to compare the efficacy and safety of Pembrolizumab plus chemotherapy (cisplatin plus fluorouracil) versus chemotherapy alone as first-line treatment for advanced esophageal and Siwert type I gastroesophageal junction cancer, showed that Pembrolizumab combined with chemotherapy was significantly superior to chemotherapy alone . Neither the KEYNOTE-062 trial nor the KEYNOTE-590 trial analyzed a separate population of patients with gastroesophageal junction cancer, and there are some differences in response to drugs by tissue type. Therefore, The efficacy of Pembrolizumab plus chemotherapy in the only patient population with gastroesophageal junction cancer warrants further investigation.