Targeted therapies in gastric cancer and future perspectives

Abstract

Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.

Keywords: Targeted therapies; Antibodies; Gastric cancer; Tyrosine kinase; Survival

Core tip: Trastuzumab was the first molecule shown to prolong both progression-free survival and overall survival in patients with advanced gastric cancer (AGC) when added to first-line chemotherapy in patients with AGC. In 2014, ramucirumab was approved as a single agent or in combination with paclitaxel for the treatment of patients with AGC. Many phase II-III clinical trials failed to showed activity of different targeted agents in patients with AGC. On the other hand, some molecules have shown promising activity in phase II trials and are expected to be in use in the coming years. Pertuzumab and c-Met pathway inhibitors have shown modest activity in a phase II trial. The results of two important ongoing phase III trials (JACOB and RILOMET-1) may change the recommendations for first-line treatment options in patients with AGC.