Bridging paradigms and shaping the future of resectable gastric cancer: a narrative review of the post-MATTERHORN era

Gastric or gastroesophageal junction cancer (GC/GEJC) ranks as the fifth leading cause of cancer-related mortality worldwide. Curative-intent surgery remains the cornerstone of treatment for locally advanced GC/GEJC. However, a substantial proportion of patients still experience disease recurrence even after complete resection. Based on the pivotal results of the FLOT4 and ESOPEC trials, perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) has been established as the standard of care for patients with locally advanced upper gastrointestinal tract adenocarcinoma, including GC/GEJC, in Western countries, whereas surgery followed by adjuvant chemotherapy remains the standard in Asia. The positive findings from the PRODIGY and RESOLVE trials have further supported neoadjuvant and perioperative strategies in Asia, fostering a trend toward global harmonization. Following the first global collaboration in KEYNOTE-585, the randomized phase III MATTERHORN trial represented a major milestone by demonstrating, for the first time, a significant improvement in event-free survival and overall survival with the addition of durvalumab to perioperative FLOT. This provided the first global phase III evidence supporting the integration of immune checkpoint inhibitors with perioperative chemotherapy in GC/GEJC. In this review, we spotlight the paradigm shift in perioperative treatment and address challenges associated with implementing FLOT plus durvalumab in daily practice. We also discuss future therapeutic directions, including molecularly targeted therapies and novel multimodal approaches. The MATTERHORN trial has set the global stage for advancing the management of resectable GC/GEJC, heralding the beginning of a new era.