MATTERHORN Trial Confirms Overall Survival Benefit, Positioning Durvalumab Plus FLOT as New Standard in Gastric Cancer

The oncology community was informed of a substantial advancement in the treatment of early-stage gastrointestinal (GI) malignancies at the European Society for Medical Oncology Congress 2025 in Berlin. Josep Tabernero, M.D., PhD., from the Vall d’Hebron Institute of Oncology, Barcelona, Spain, presented the final overall survival (OS) results from the global, double-blind, Phase III MATTERHORN trial (NCT04592913).

The study, which began enrolling patients in late 2020 and included nearly 1,000 participants worldwide, evaluated both neoadjuvant (pre-surgery) and adjuvant (post-surgery) use of durvalumab (Imfinzi) in combination with FLOT chemotherapy.

This study assessed the efficacy of durvalumab in the standard perioperative chemotherapy regimen FLOT—which includes fluorouracil, leucovorin, oxaliplatin, and docetaxel—for patients with resectable gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. The data analysis confirmed a statistically significant overall survival advantage over chemotherapy alone, thereby strongly supporting the prospective new standard of care of durvalumab in conjunction with FLOT chemotherapy.

Gastric and G/GEJ cancers are a main cause of cancer mortality worldwide. For patients with resectable disease, perioperative FLOT chemotherapy is the current standard of care. Nevertheless, recurrence rates are considerable, with over half of patients eventually relapsing after curative surgery, despite this aggressive course of action.

Efforts to incorporate immune checkpoint inhibitors, such as the PD-L1 inhibitor durvalumab, earlier in the treatment of metastatic disease have been motivated by their effectiveness in reducing recurrence and improving cure rates in the perioperative setting.

The MATTERHORN trial was established to determine whether the addition of durvalumab to FLOT could improve long-term survival and anti-tumor activity in patients with resectable, early-stage, and locally advanced gastric and gastroesophageal junction (GEJ) malignancies (Stages II, III and IVA) in comparison to chemotherapy alone.

The study randomized 948 patients with resectable, locally advanced G/GEJ adenocarcinoma 1:1. Participants received either durvalumab 1500 mg or placebo, combined with FLOT every two weeks for four perioperative cycles (two pre- and two postoperative), followed by ten additional cycles of durvalumab or placebo monotherapy. Event-free survival (EFS) was the primary endpoint, with OS serving as a key secondary endpoint.

Earlier interim results, published in the Journal of Clinical Oncology in June 2025 by investigators, had already shown that D + FLOT significantly improved EFS (HR 0.71; p<0.001).

The final OS analysis presented at ESMO 2025 provided the conclusive evidence: durvalumab + FLOT demonstrated a statistically significant and clinically meaningful OS improvement compared with placebo + FLOT (HR 0.78; 95% CI 0.63–0.96; p = 0.021).

Crucially, the treatment effect was found to be independent of PD-L1 expression, demonstrating similar hazard ratios across both low and high expression subgroups. Furthermore, significant tumor regression was observed in patients treated with durvalumab, as the treated group achieved significantly higher nodal negativity rates. The comprehensive benefit of the addition of immunotherapy was underscored by the observation of EFS improvements across all levels of pathological response.

The role of durvalumab + FLOT as a prospective new global standard of care for patients undergoing curative-intent treatment for gastric and GEJ adenocarcinoma is further solidified by these findings, which reinforce the expanding utility of checkpoint inhibition in early-stage GI oncology.