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

// Lihong Huang 1,* , Yongyue Wei 1,* , Sipeng Shen 1 , Qianwen Shi 1 , Jianling Bai 1 , Jin Li 3 , Shukui Qin 4 , Hao Yu 1 and Feng Chen 1,2,** 1 Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, P.R. China 2 Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, P.R. China 3 Fudan University Shanghai Cancer Center, Shanghai, P.R. China 4 People’s Liberation Army Cancer center, 81st Hospital of People’s Liberation Army, Nanjing, Jiangsu, P.R. China * These authors have contributed equally to this work ** Senior author Correspondence to: Hao Yu, email: // Shukui Qin, email: // Keywords : apatinib, gastric cancer, overall survival, progression-free survival, mediation analysis Received : September 02, 2016 Accepted : October 17, 2016 Published : October 25, 2016 Abstract 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.