Comparative efficacy and tolerability of first-line treatments for untreated, HER2-negative, advanced gastric cancer: systematic review and network meta-analysis

This article provided direct comparisons across first-line regimens for patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer. We performed a network meta-analysis (NMA) of phase III trials to compare the efficacy and safety of first-line treatments for gastric cancer. We conducted a systematic review and Bayesian or Frequentist network meta-analysis by searching relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences from January 1, 2000 to May 1, 2023. This study was registered in the Prospective Register of Systematic Reviews (PROSPERO CRD42023414357) to ensure transparency. Randomized clinical trials (RCTs) that qualified the inclusion criteria were subjected to network meta-analysis and systematically reviewed. We included a total of 25 studies including 14389 patients and 23 first-line treatments. Overall, sintilimab plus capecitabine plus oxaliplatin (Sint-XELOX) appeared to confer the best overall survival (OS) (calculated using surface under the cumulative ranking curve [SUCRA], 81%), with significant differences versus fluorouracil plus cisplatin (PF) (HR [hazard ratios] = 0.71, 95% credible interval [CI]: 0.51–0.99). Nivolumab plus tegafur (S-1) plus oxaliplatin (Nivo-SOX) and tislelizumab plus capecitabine plus oxaliplatin (Tisle-XELOX) were also found to be better than PF in providing OS benefit (HR = 0.73, 95%CI: 0.57–0.93 and HR = 0.74, 95%CI: 0.59–0.93, respectively). Sint-XELOX still provided the best progression-free survival (PFS) (SUCRA, 96%), with significant differences versus PF (HR = 0.47, 95%CI: 0.31–0.69). Nivo-SOX and Tisle-XELOX were also found to be better to PF in providing PFS benefit (HR = 0.58, 95%CI: 0.42–0.80 and HR = 0.67, 95%CI: 0.54–0.82, respectively). These results indicated that immunotherapy plus chemotherapy was associated with greater progression-free survival and overall survival benefits for patients with HER2-negative advanced gastric cancer, compared with other first-line treatments. In particular, sintilimab combined with chemotherapy showed the best PFS and OS benefits.