Gastric cancer remains a major global health burden, ranking among the top five cancers worldwide in both incidence and mortality. Despite advances in surgery and systemic therapy, survival in locally advanced disease lags behind that of other common malignancies, such as colorectal or breast cancer. For stage 3 tumors, the five-year survival rate hovers just above 50%, underscoring the urgent need for new strategies. At the 36^th ASCOMOS, Dr. Wan Zamaniah Wan Ishak, consultant clinical oncologist at Universiti Malaya Medical Centre (UMMC), Kuala Lumpur, explored the evolving treatment landscape, highlighting how immunotherapy is beginning to redefine the curative setting for gastric and gastroesophageal junction (GEJ) cancers.

Traditionally, curative intent for gastric and GEJ cancers has long relied on chemotherapy, delivered either in the perioperative setting or as adjuvant therapy following surgery, with regional differences in practice. In Japan and Korea, upfront surgery followed by adjuvant chemotherapy remains a standard approach, whereas international guidelines increasingly endorse perioperative strategies. Landmark trials such as MAGIC and CLASSIC established chemotherapy as the backbone of curative treatment, a foundation later refined by the AIO-FLOT4 study, which demonstrated a survival advantage of the FLOT regimen (5-FU, leucovorin, oxaliplatin, docetaxel) over the older ECF regimen (epirubicin, cisplatin, and 5-fluorouracil). More recently, the ESOPEC trial confirmed the superiority of perioperative FLOT over chemoradiotherapy (CRT) with CROSS (41.4Gy + carboplatin/paclitaxel) in resectable GEJ adenocarcinoma. Together, these studies cemented perioperative FLOT as a global reference standard, though questions remained as to whether outcomes could be further improved.

The integration of immunotherapy into earlier disease stages is now one of the most promising frontiers. Gastric and GEJ tumors often exploit the PD-1/PD-L1 pathway for immune evasion, providing a clear rationale for checkpoint inhibition in this setting. Recent phase 3 trials have tested immune checkpoint inhibitors (ICIs) with chemotherapy in the perioperative or adjuvant context, producing results that are both encouraging and nuanced.

The MATTERHORN trial evaluated durvalumab in combination with perioperative FLOT (D-FLOT) in resectable gastric or GEJ adenocarcinoma. At a median follow-up of 31.6 months, durvalumab significantly improved the primary endpoint of event-free survival (EFS) (not reached [NR] vs. 32.8 months; HR=0.71; 95% CI: 0.58-0.86). Disease-free survival (DFS), a secondary endpoint, was also improved with D-FLOT compared with FLOT alone (NR vs. 39.8 months; HR=0.70; 95% CI: 0.53-0.93). Pathological complete response (pCR) rates were higher in the durvalumab arm, with consistent benefits across subgroups and geographic regions. Safety findings revealed no new signals beyond known durvalumab-related toxicities. According to Dr. Wan Zamaniah, with the separation of survival curves as early as two months, MATTERHORN supports the global adoption of perioperative D-FLOT as a new standard for patients with localized gastric and GEJ adenocarcinoma.

Dr. Wan Zamaniah also shared findings from the phase 3 KEYNOTE-585 trial, which enrolled patients with previously untreated, locally advanced, resectable gastric or GEJ adenocarcinoma. Patients were randomized to receive pembrolizumab + perioperative chemotherapy or placebo + chemotherapy (n=402 per arm in the cisplatin/5-FU main cohort; a smaller cohort received FLOT). At a median follow-up of 47.7 months, pembrolizumab + chemotherapy significantly improved pCR rates compared with chemotherapy alone (12.9% vs. 2%; absolute difference: 10.9%, p<0.00001). Median EFS was longer with pembrolizumab, although this did not meet the trial’s prespecified threshold for statistical significance (44.4 months vs. 25.3 months; HR=0.81; 95% CI: 0.67-0.99; p=0.0198). While toxicities were manageable and consistent with prior pembrolizumab experience, the lack of a defined EFS advantage underscores the need for further studies to clarify its role in this setting.

In the adjuvant-only setting, ATTRACTION-5 evaluated nivolumab + chemotherapy after surgery in stage 3 gastric or GEJ cancer but did not demonstrate an improvement in relapse-free survival. The VESTIGE study, which assessed immunotherapy following perioperative chemotherapy and surgery in high-risk patients, reported similar outcomes—suggesting that checkpoint blockade may be less effective when delayed until after surgery. On the other hand, early phase data from DANTE, evaluating atezolizumab with FLOT, reinforce the feasibility of immunotherapy combinations, with encouraging signals but pending mature survival data. Taken together, these findings point to a paradigm shift that is both promising and complex.

Dr. Wan Zamaniah emphasized that the most compelling evidence to date comes from MATTERHORN, where D-FLOT provided clinically meaningful benefit without compromising safety. KEYNOTE-585 demonstrated improvement in pathologic response, but translating this into durable survival gains remains a challenge. The outcomes from ATTRACTION-5 and VESTIGE underscore the importance of timing and patient selection, raising the possibility that immunotherapy may be most effective when introduced upfront rather than reserved for the postoperative setting.

In conclusion, perioperative chemotherapy continues to anchor curative treatment for locally advanced gastric and GEJ cancer, with FLOT as the global benchmark. Immunotherapy is beginning to add incremental value, and D-FLOT may redefine the standard once survival benefit is confirmed. Yet the variability across trials cautions against a one-size-fits-all approach. As Dr. Wan Zamaniah noted, “adoption into practice will depend not only on clinical trial outcomes but also on real-world considerations such as patient fitness, access, and affordability to treatment options”. The new frontier in gastric cancer care, therefore, lies not simply in adding immunotherapy, but in integrating it wisely into the curative pathway.