Systemic therapy beyond first-line in advanced gastric cancer: An overview of the main randomized clinical trials

•Progressive gastric cancer patients may benefit from a second-line therapy.•Monochemotherapy (both irinotecan and taxanes) is superior to BSC.•Novel targeted agents such as ramucirumab and apatinib are really promising.•Ramucirumab is the first targeted drug approved by FDA and EMA in second-line.•Future investigation should provide stronger predictive markers to targeted therapy.

Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies.