Final MATTERHORN Analysis Confirms Overall Survival Benefit With Durvalumab Plus FLOT in Resectable Gastric Cancer

A final analysis of the phase 3 MATTERHORN trial ((NCT04592913) confirms that adding durvalumab to perioperative FLOT chemotherapy improves overall survival (OS) in patients with resectable gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. The findings, published in The Lancet, extend previously reported improvements in event-free survival (EFS) and pathological complete response (pCR).

Final Analysis Confirms Overall Survival Benefit

MATTERHORN enrolled 948 adults with stage II–IVa resectable gastric or GEJ adenocarcinoma across 147 centres in 20 countries. Patients were randomly assigned to durvalumab 1500 mg or placebo every four weeks, combined with FLOT every two weeks for four cycles two before surgery and two after surgery followed by 10 additional cycles of durvalumab or placebo.

After a median follow-up of approximately 41 months, the final analysis showed a statistically significant reduction in the risk of death with durvalumab plus FLOT. OS improved with a hazard ratio (HR) of 0.78 (95% CI, 0.63–0.96; P=0.021), representing a 22% relative reduction in the risk of death. At 24 months, 76% of patients receiving durvalumab remained alive versus 70% with placebo; at 36 months, survival was 69% versus 62%. Median OS was not reached in either group.

Benefit Across PD-L1 Expression

The survival benefit was not restricted to patients with higher PD-L1 expression. OS numerically favoured durvalumab in both patients with tumour area positivity (TAP) ≥1% and those with TAP <1%, with an HR of 0.79 in each subgroup. However, the trial was not powered for definitive individual subgroup comparisons, so these findings should be interpreted cautiously.

Pathological Responses Also Improved

The final central pathology analysis further strengthened the evidence for adding durvalumab. pCR occurred in 24% of patients receiving durvalumab versus 9% with placebo, corresponding to an odds ratio of 3.08 (95% CI, 2.01–4.70). Major pathological response was also more frequent with durvalumab, at 33% versus 18%.

These findings build on the earlier primary analysis, which showed a 29% reduction in the risk of an EFS event or death (HR 0.71; 95% CI, 0.58–0.86; P<0.001).

Safety and Surgical Feasibility

Safety remained broadly consistent with the known profiles of the treatment components. Grade 3 or 4 adverse events occurred in 72% of patients receiving durvalumab versus 71% with placebo. Immune-mediated adverse events were more frequent with durvalumab, occurring in 23% versus 7%, but no new safety signals emerged. Surgery was not compromised, with similar rates of surgical completion and complete resection between groups.

Clinical Implications

The final MATTERHORN results provide mature evidence that perioperative durvalumab plus FLOT can improve survival while increasing tumour response without compromising surgical feasibility. Based on earlier MATTERHORN results, the regimen has already received approval in the United States for adults with resectable gastric or GEJ adenocarcinoma.

The remaining clinical challenge is identifying patients who derive limited pathological benefit from perioperative therapy and determining whether treatment should be adapted for these nonresponders. Further follow-up and biomarker analyses will help define how best to individualize perioperative treatment.

Reference

Janjigian Y, Al-Batran S, Wainberg Z et al., Perioperative durvalumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable gastric and gastro oesophageal junction adenocarcinoma (MATTERHORN): final results of overall survival and event-free survival by pathological response in a global, randomised, double-blind, placebo-controlled, multicentre, phase 3 trial, The Lancet, Published September 9, 2026, https://doi.org/10.1016/S0140-6736(26)01254-7