Therapeutic effect of apatinib on overall survival is mediated by prolonged progression-free survival in advanced gastric cancer patients

Apatinib is reported to significantly improve the overall survival (OS) of patients with advanced gastric cancer who have previously failed second-line chemotherapy. However, it is not well understood whether apatinib acts by improving progression or by prolonging post-progression survival. Here, based on phase III clinical trial data, the mediating effect of apatinib on patient overall survival was systematically quantified, through progression-free survival (PFS), post-progression survival (PPS), and the disease control rate (DCR). PFS was the primary mediator of the association between apatinib treatment and OS, with an indirect-effect mean survival time ratio of 1.63 (95%CI 1.35-1.97), which mediated 93.5% of the treatment effect. The DCR was also a significant mediator among secondary efficacy endpoints, and had an indirect-effect mean survival time ratio of 1.47 (95%CI 1.20-1.79, 50.9% mediated). Both primary and other targets of the DCR had similar results. The results indicated that apatinib treatment prolongs progression-free survival rather than post-progression survival, and in turn, leads to improved overall survival. Additionally, our study highlights the value of mediation analysis in clinical trials in providing additional information to build upon traditional primary analysis.