Shifting paradigm in locally advanced resectable gastric and gastroesophageal junction cancers

Gastric cancer (GC) is the fifth most common cancer and the fifth leading cause of cancer-related mortality worldwide. The management of resectable locally advanced GC evolved with the introduction of adjuvant chemoradiotherapy in some regions, notably following the INT-0116 trial. A subsequent major advance was perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil, which significantly improved 5-year overall survival compared to surgery alone. More recently, the fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen demonstrated superior outcomes compared to epirubicin, cisplatin, and fluorouracil. Despite this advancement, nearly half of all patients (46%) experience disease recurrence within three years, underscoring a significant unmet need. In a recent real-world study by Wang et al, which assessed perioperative sintilimab plus oxaliplatin and S-1 chemotherapy vs chemotherapy alone in non-metastatic GC, the authors reported significantly improved pathological response rates and overall survival with the combination. Additionally, the safety profile showed a lower frequency of high-grade adverse events. However, this study has limitations, including its retrospective design and the use of a chemotherapy backbone (oxaliplatin and S-1) considered less effective than FLOT based on phase III evidence. Recent data from the phase III MATTERHORN trial support the addition of durvalumab to FLOT, showing significant improvements in pathological complete response and event-free survival. Based on the cumulative evidence, adding immunotherapy to perioperative chemotherapy improves outcomes for patients with resected GC and may constitute a new standard of care once confirmatory data mature and regulatory approvals are granted.