MATTERHORN Final OS: Perioperative Durvalumab Plus FLOT Cuts Death Risk 22% in Resectable Gastric/GEJ Cancer
核心洞察
Final overall survival results from the phase 3 MATTERHORN trial show perioperative durvalumab plus FLOT reduced the risk of death by 22% versus placebo plus FLOT.
At a median follow-up of 43 months, 69% of durvalumab-treated patients were alive at three years versus 62% in the control group.
The overall survival benefit was consistent across most subgroups, including regardless of PD-L1 (搜索) expression status, and appeared more pronounced in node-positive disease.
Adding perioperative durvalumab (Imfinzi) to standard FLOT chemotherapy significantly improved overall survival (OS) compared with placebo plus FLOT in patients with resectable, localized gastric or gastroesophageal junction (GEJ) cancer, according to final OS results from the global, randomized phase 3 MATTERHORN trial published in The Lancet.
The regimen reduced the risk of death by 22% (HR, 0.78; 95% CI, 0.63-0.96; P = .021; significance threshold P < .0499), meeting the trial's key secondary end point after MATTERHORN had previously met its primary end point of event-free survival (EFS). The study was co-directed by Josep Tabernero, MD, head of the Medical Oncology Department at Vall d'Hebron University Hospital and director of the Vall d'Hebron Institute of Oncology (搜索).
Survival Outcomes at 43 Months
At a median follow-up of approximately 43 months and a data cutoff of September 1, 2025, 160 of 474 patients (34%) in the durvalumab group and 192 of 474 (41%) in the placebo group had died. Median OS was not reached in either group, with OS maturity at 37%.
OS rates were 76% (95% CI, 71%-79%) with durvalumab versus 70% (95% CI, 66%-74%) with placebo at 24 months, and 69% (95% CI, 64%-73%) versus 62% (95% CI, 57%-66%) at 36 months. The OS benefit favored durvalumab across most clinically relevant subgroups and appeared more pronounced in patients with node-positive disease (HR, 0.73; 95% CI, 0.57-0.94) than in the node-negative subgroup (HR, 1.01; 95% CI, 0.67-1.51). A numerical OS improvement was observed regardless of PD-L1 (搜索) expression status (tumor area positivity [TAP] of at least 1%: HR, 0.79; 95% CI, 0.63-0.99; TAP of less than 1%: HR, 0.79; 95% CI, 0.41-1.50).
"These results position this perioperative regimen as the first immunotherapy strategy to demonstrate prolonged survival in patients with early-stage gastric or gastroesophageal junction cancer (搜索), and point to a new standard of care," Tabernero said.
Pathological Response and Event-Free Survival
In the central pathology analysis set, a pathological complete response (pCR) was reached in 91 of 385 patients (24%) in the durvalumab group versus 34 of 372 (9%) in the placebo group (OR, 3.08; 95% CI, 2.01-4.70). In post-hoc exploratory analyses, EFS numerically favored durvalumab regardless of the degree of pathological response, including among patients who achieved a pCR (HR, 0.29; 95% CI, 0.08-0.96), a major pathological response (HR, 0.32; 95% CI, 0.15-0.68), and any pathological response (HR, 0.60; 95% CI, 0.46-0.79). The authors cautioned that the pCR analysis was based on 11 events, producing a wide confidence interval that warrants careful interpretation.
The primary end point of EFS was previously reported to be significantly improved with durvalumab (HR, 0.71; 95% CI, 0.58-0.86; P < .001).
Trial Design and Patient Population
MATTERHORN is a double-blind, placebo-controlled phase 3 trial conducted at 147 centers across 20 countries in Europe, Asia, North America, and South America. A total of 948 adults with treatment-naive, resectable stage II to IVa gastric or GEJ adenocarcinoma were randomly assigned 1:1 to perioperative durvalumab plus FLOT or placebo plus FLOT.
Patients received durvalumab at 1500 mg or placebo intravenously every 4 weeks plus FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) every 2 weeks for 4 cycles (2 neoadjuvant and 2 adjuvant), followed by durvalumab or placebo every 4 weeks for 10 additional cycles. OS in the intention-to-treat population was the key secondary end point reported in this analysis.
Safety Profile
Safety outcomes, reported previously at a data cutoff of December 20, 2024, were consistent with the known profiles of durvalumab and FLOT, with no new safety signals. Any-grade adverse events (AEs) occurred in 99% of patients in both groups, and maximum grade 3 or 4 AEs occurred in 72% of the durvalumab group versus 71% of the placebo group. Serious AEs occurred in 48% versus 44% of patients, respectively, and AEs leading to discontinuation of any trial treatment occurred in 30% versus 23%. AEs with an outcome of death possibly related to any trial treatment occurred in 6 patients (1%) in the durvalumab group and 2 (less than 1%) in the placebo group. Any-grade immune-mediated AEs occurred in 23% of the durvalumab group versus 7% of the placebo group.
Clinical Context and Regulatory Status
Gastric cancer (搜索) is the fifth most common cancer worldwide and accounts for nearly 5% of all new cancer diagnoses, with almost one million new cases annually. It has a particularly high incidence in people over the age of 65 and is approximately twice as common in men as in women.
"Complete surgical resection is the cornerstone of treatment for localized gastric or gastroesophageal junction cancer (搜索). In most Western countries, the FLOT three-drug chemotherapy regimen is the standard-of-care for this patient population, given before and after surgery," Tabernero said. "While advances in treatment have improved survival, the prognosis of patients with gastric cancer (搜索) is often poor. Due to late-stage diagnosis and the aggressive nature of the disease, the overall five-year survival rate is 33% in the U.S. and 25% globally, representing an unmet clinical challenge."
Based on results from the MATTERHORN trial, the European Medicines Agency (搜索) approved the use of durvalumab in combination with chemotherapy last March as the first and only perioperative immunotherapy for patients with early-stage gastric or gastroesophageal junction cancer (搜索). The indication is already approved in the United States and other countries, while regulatory applications remain under review in Japan and other markets.