Phase III Trial Comparing XELOX Regimen (Oxaliplatin Plus Capecitabine) Versus EOX Regimen (Epirubicin, Oxaliplatin and Capecitabine) as First-Line Treatment for Advanced Gastric Cancer: The EXELOX Trial

Abstract

Background: It’s still controversial whether triplet is better than doublet regimen in first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of new generation doublet regimen XELOX and EOX triplet regimen. Methods: EXELOX was an open-label, multicenter, randomized phase III trial that enrolled 448 previously untreated patients with AGC. Patients were randomly assigned to receive XELOX or EOX regimen. The primary endpoint was noninferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. The second endpoints included overall survival(OS), objective response rate(ORR), safety, and quality of life (QoL). This study is registered with ClinicalTrials.gov, number NCT02395640. Findings: Between Apr 10, 2015 and Aug 20,2020, 448 AGC patients were randomized to receive XELOX (n=222) or EOX (n=226). In ITT basis, the median PFS was 5.0 months (95%CI 4.5-6.0) in XELOX group and 5.5 months (95%CI 5.0-6.0) in EOX group (HR 0.989, 95%CI 0.812-1.203; Pnon-inferiority =0.0032). There was no significant difference in median OS (12.0 vs. 12.0 months, HR 1.097, p =0.384), or ORR(37.4% vs. 45.1%, p =0.291) between two groups. In patients with poor differentiated adenocarcinoma and liver metastasis, EOX arm had significant longer mOS(p=0.021) and trend of longer mPFS(p=0.073) than XELOX arm. The incidence of grade 3/4 adverse events (AEs) was 42.2% (90/213) in XELOX group and 72.5% (156/215) in EOX group (p=0.001). The Global Health/QoL score were significantly higher in XELOX group than EOX group during chemotherapy. Interpretation: This is the first noninferiority trial demonstrating that doublet is as effective as triplet regimen generally, with a better safety profile and QoL as first-line treatment for AGC patients; but triplet regimen might have effects advantage in selected subsets, providing solid evidence for guideline update and guidance for future clinical trial design. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT02395640 . Funding: This study was supported by The National Key Research and Development Program of China [grant no. 2017YFC1308900]; The clinical research and cultivation project of shanghai Shenkang hospital development center [grant no. SHDC12017X01] and Sun Yat-sen University Xie Tong Chuang Xin Program [grant no. ZLYXXTCX201504]. Declaration of Interest: None to declare. Ethical Approval: The trial protocol was approved by the local institutional review board and ethics committee.