Perioperative Durvalumab Combo Boosts Survival in Resectable Gastric Cancer

Perioperative durvalumab (Imfinzi) plus fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) significantly improved overall survival (OS) vs placebo plus FLOT in patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to final OS results from the phase 3 MATTERHORN trial (NCT04592913) published in The Lancet.¹

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 key secondary end point of OS after the trial previously met its primary end point of event-free survival (EFS).

What did the final MATTERHORN overall survival analysis show?

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%. The OS rate was 76% (95% CI, 71%-79%) with durvalumab vs 70% (95% CI, 66%-74%) with placebo at 24 months, and 69% (95% CI, 64%-73%) vs 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 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).

“Complete surgical resection is the cornerstone of treatment for localized gastric or gastroesophageal junction cancer. In most Western countries, the FLOT 3-drug chemotherapy regimen is the standard-of-care for this patient population, given before and after surgery. While advances in treatment have improved survival, the prognosis of patients with gastric cancer is often poor. Due to late-stage diagnosis and the aggressive nature of the disease, the overall 5-year survival rate is 33% in the US and 25% globally, representing an unmet clinical challenge,” senior study author 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, stated in a press release regarding these findings.² “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, and point to a new standard of care.”

How did pathological response relate to outcomes?

In the central pathology analysis set, a pathological complete response (pCR) was reached in 91 of 385 patients (24%) in the durvalumab group vs 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.

What was the safety profile of perioperative durvalumab plus FLOT?

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 vs 71% of the placebo group. Serious AEs occurred in 48% vs 44% of patients, respectively, and AEs leading to discontinuation of any trial treatment occurred in 30% vs 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 vs 7% of the placebo group.

What is the MATTERHORN trial design and regulatory context?

MATTERHORN is a global, randomized, double-blind, placebo-controlled, phase 3 trial conducted at 147 centers across 20 countries. 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 every 2 weeks for 4 cycles (2 neoadjuvant and 2 adjuvant), followed by durvalumab or placebo every 4 weeks for 10 additional cycles.

The primary end point was EFS, previously reported to be significantly improved with durvalumab (HR, 0.71; 95% CI, 0.58-0.86; P <.001); OS in the intention-to-treat population was the key secondary end point reported in this analysis.³

References

1. Janjigian YY, Al-Batran SE, Wainberg ZA, 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. Lancet. Published online September 9, 2026. doi:10.1016/S0140-6736(26)01254-7
2. Final overall survival results of the phase 3 MATTERHORN study support perioperative immunotherapy as a new standard treatment option for resectable, localized gastric or gastroesophageal junction cancer. News release. Vall d’Hebron Institute of Oncology (VHIO). September 10, 2026. Accessed September 11, 2026. https://tinyurl.com/ypp57nme
3. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med. 2025;393(3):217-230. doi:10.1056/NEJMoa2503701