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Durvalumab Added to Perioperative FLOT Significantly Improves Overall Survival in Resectable Gastric Cancer
In a global phase 3 trial of 948 patients with resectable gastric or gastro-oesophageal junction adenocarcinoma, adding durvalumab to perioperative FLOT chemotherapy reduced the risk of death by approximately 22% compared with FLOT alone — about 22% lower risk of death (HR 0.78, 95% CI 0.63–0.96; p=0.021). This statistically significant overall survival benefit, crossing a pre-specified threshold of p<0.0499, supports the authors’ conclusion that perioperative durvalumab plus FLOT represents a new standard-of-care option in this setting.
What Was Studied
The MATTERHORN trial investigated whether adding the PD-L1 immune checkpoint inhibitor durvalumab to the established perioperative FLOT chemotherapy regimen could improve overall survival in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. This publication reports the key secondary endpoint of overall survival, following the previously published primary endpoint of event-free survival, which had already shown benefit with the durvalumab combination.
How It Was Studied
MATTERHORN is a global, randomised, double-blind, placebo-controlled, multicentre phase 3 trial conducted across 147 medical centres in 20 countries spanning Asia, Europe, North America, and South America. A total of 948 adults with histologically confirmed, previously untreated resectable gastric or gastro-oesophageal junction adenocarcinoma at clinical stage II–IVa were enrolled between November 2020 and September 2022, and were randomly assigned 1:1 to receive either durvalumab 1500 mg intravenously every four weeks or matched placebo, layered onto the standard FLOT backbone given every two weeks for four perioperative cycles. Following surgery, both arms continued their assigned immunotherapy or placebo for an additional ten cycles of durvalumab or placebo every four weeks. Randomisation was stratified by geographic region, clinical lymph node status, and PD-L1 expression, with participants, investigators, and outcome assessors all masked to treatment allocation.
What Was Observed
- Overall survival was significantly improved in patients receiving durvalumab plus FLOT compared with placebo plus FLOT — approximately 22% lower risk of death (HR 0.78, 95% CI 0.63–0.96; p=0.021), surpassing the pre-specified significance threshold of p<0.0499. Median overall survival values were not reported in the abstract, which limits full characterisation of the absolute magnitude of benefit.
- Event-free survival had previously been demonstrated to improve with durvalumab plus FLOT, and a higher rate of pathological complete response was also reported in earlier analyses of this trial. The current publication confirms that the earlier surrogate endpoint benefits translated into a statistically significant improvement in the ultimate clinical outcome of overall survival.
- Treatment-related mortality was low in both arms, though slightly higher in the durvalumab group: adverse events with a fatal outcome possibly related to trial treatment occurred in 6 participants (1%) in the durvalumab arm compared with 2 participants (<1%) in the placebo arm, a difference that remains a small absolute number in the context of this population size.
Why This Matters
MATTERHORN is, according to the authors, the first phase 3 trial to demonstrate that incorporating a PD-L1 inhibitor into a perioperative chemotherapy regimen confers a statistically significant overall survival advantage in resectable gastric and gastro-oesophageal junction adenocarcinoma. The trial enrolled a geographically diverse population across four continents, enhancing the potential generalisability of the findings. The authors explicitly state that perioperative durvalumab plus FLOT now constitutes a new standard treatment option for patients with this diagnosis.
How to Read This Result
This large, well-designed, double-blind phase 3 trial provides high-quality evidence of an overall survival benefit, though the absence of reported median survival times and the relatively modest width of the confidence interval (0.63–0.96) suggest that the true magnitude of benefit warrants careful interpretation, and the trial remains ongoing.
Limitations
The abstract does not explicitly report study limitations.