Efficacy and Safety of Apatinib Combined with S-1 Plus Oxaliplatin as Neoadjuvant Treatment for Locally Advanced Gastric Cancer: A Multicenter, Prospective Study

Abstract

Background: Apatinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2), is a novel treatment option for advanced gastric cancer (AGC) refractory to two or more lines of prior chemotherapy but has not yet been evaluated in patients with locally AGC. This trial investigated the efficacy and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally AGC. Methods: Patients with M0 and either T2-T4 or N+ disease received apatinib (500 mg orally once daily on days 1-21 and discontinued in the last cycle) plus SOX (S-1, 40-60 mg orally twice daily on days 1-14; oxaliplatin, 130 mg/m2 intravenously on day 1) given every 3 weeks for 2-5 cycles. D2 gastrectomy was performed 2-4 weeks after the last cycle. To further compare the efficacy and safety between apatinib plus SOX (ASOX group) and SOX alone (SOX group), we reviewed historical control patients receiving SOX as neoadjuvant chemotherapy at the central center. The primary end point was the R0 resection rate. Findings: Between July 2017 and June 2019, 48 and 58 patients were enrolled in the ASOX and SOX groups, respectively. Forty patients in the ASOX group (83.3%) and 47 patients in the SOX group (81.0%) underwent surgery, with R0 resection rates of 75.0% and 67.2%, respectively (P=0.382). For patients proceeding surgery, the R0 resection rates were 90.0% (36/40) and 82.3% (39/47), respectively (P = 0.534). The proportion of patients with T downstaging in the ASOX group was significantly higher than that in the SOX group (36.4% vs 18.5%, P=0.036). For patients with target lesions, the radiological response rate was significantly higher in the ASOX group (75.0% vs 38.5%, P=0.015). Moreover, the ASOX group was associated with significantly higher proportions of patients achieving major pathological response (25.0% vs 10.3%, P=0.046). Grade 3 toxicities occurred in 33.3% of the ASOX patients, and no grade 4 toxicities or drug-related deaths were observed. Interpretation: Apatinib combined with SOX showed promising efficacy with an acceptable safety profile as the first-line neoadjuvant treatment for locally AGC. Trial Registration: The trial is registered with ClinicalTrials.gov, number NCT03192735. Funding Statement: This study was supported by Scientific and technological innovation joint capital projects of Fujian Province, China (No.2017Y9011, No.2017Y9004). Minimally invasive medical center of Fujian Province (No. [2017]171). National natural science foundation of China (No.81871899). The second batch of special support funds for Fujian Province innovation and entrepreneurship talents (No.2016B013). Declaration of Interests: There are no conflicts of interest or financial ties to disclose from any authors. Ethics Approval Statement: The informed consent form and study protocol were approved by the Institutional Review Boards of each participating institution. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and Chinese law. All patients provided written informed consent before enrollment.