Gastric cancer (GC) is a disease of global importance. With over 1 million estimated new cases annually, gastric cancer is the fifth most diagnosed malignancy worldwide. Due to its frequently advanced stage at diagnosis, mortality from gastric cancer is high, making it the third most common cause of cancer-related deaths (Elizabeth et al., 2020). The incidence of gastric cancer is remarkably higher in East Asia, including South Korea and Japan, than in other world regions (International Agency for Research on Cancer, 2021). Despite considerable improvements in surgical and comprehensive therapies, the 5-year survival rate remains dismally low, estimated at 20% for advanced GC (Rawla and Barsouk, 2019). Combined chemotherapy with fluoropyrimidine (e.g.5-fluorouracil and capecitabine) and platinum (e.g. cisplatin and oxaliplatin) has been recommended as the standard of care for HER2-negative advanced GC in the first-line treatment (Lee et al., 2021, Kang et al., 2020). However, The median progression-free survival (PFS) and the median overall survival (OS) in the patient group have been reported as 1.9–6.0 months and 10.5–14.1 months, respectively (Koizumi, et al., 2008; Yoon-Koo et al., 2022). Given the prevalence and dismal outcomes associated with advanced GC, global researchers have been working ceaselessly to develop new interventions and combinations to prolong the lifespan of patients.

Over a decade ago, combination therapy with the anti–HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for these patients (Bang et al., 2010) with HER2-positive advanced gastric cancer, and it could significantly improve the quality of life of patients and prolong their survival period. For HER2-negative advanced gastric cancer, chemotherapy has entered the bottleneck period, and targeted therapy options are limited. Immunotherapy is one of the most important breakthroughs in cancer treatment, and the programmed cell death (PD)− 1 inhibitor provided superior OS versus placebo in heavily pre-treated advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma in several phase 3 studies (Kang et al., 2017). In this study, four major immunotherapy combination regimens have been explored as first-line treatment. Anti-programmed cell death 1 (PD-1) plus chemotherapy combinations have been validated as an effective option in Checkmate-649, Orient-16, and Rationale-305. Clinical evidence has revealed that sintilimab, nivolumab, and tislelizumab provide additional benefits in both OS and PFS when compared with standard chemotherapy as the first-line treatment for patients with HER2-negative advanced gastric cancer (Yelena et al., 2021; Xu et al., 2021; Markus et al., 2023). In addition, although targeted therapy combined with chemotherapy can improve the PFS of patients, it fails to improve the OS and even increases the toxicity. Such as ramucirumab, an anti-vascular endothelial growth factor (VEGF) receptor-2 can improve the PFS for patients with HER2-negative advanced gastric cancer (Charles et al., 2019). Bevacizumab combined with chemotherapy has been validated as an effective treatment option (Atsushi et al., 2011). However, combining certain targeted drugs on the basis of standard chemotherapy not only fails to achieve satisfactory efficacy but also increases toxicity, for instance, panitumumab, cetuximab, and andecaliximab (Tom Waddell et al., 2013; Florian et al., 2013; Manish et al., 2020). In addition to adding new treatment methods to the chemotherapy regimen, adding a chemotherapy drug can also show survival advantages for advanced gastric cancer. V325 study showed that adding docetaxel to cisplatin and fluorouracil significantly improved time to progression (TTP), survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity (Eric et al., 2006). Sometimes it's not true that the more medication you take, the better the effect: the addition of docetaxel to cisplatin and S-1 did not improve overall survival in chemotherapy-naïve Japanese patients with advanced gastric cancer (Yasuhide et al., 2019).

To support clinical decision-making in an increasingly complex setting, we directly compared the efficacy and safety data of randomized controlled first-line trials for HER2-negative advanced gastric cancer using a network meta-analysis.