Clinical trialPhase 3Stomach cancerOesophageal cancer

Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer

N Engl J Med · 2025948 patients (474 durvalumab + FLOT and 474 placebo + FLOT)

Janjigian YY, Al-Batran SE, Wainberg ZA, et al. N Engl J Med. 2025. 393:217-230

A newer report of this study has been published: 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 (2026)

Study type: Clinical trial
Study name: MATTERHORN
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled, multinational trial (1:1 randomisation)
Sample size: 948 patients (474 durvalumab + FLOT and 474 placebo + FLOT)
Source: N Engl J Med · 2025
Trial registration: NCT04592913

In plain words

Even with the best chemotherapy before and after surgery (FLOT), stomach cancer comes back in many patients. In this study, adding the immunotherapy drug durvalumab to FLOT, and continuing it on its own after surgery, raised the chance of being alive without the disease returning or progressing at two years from about 59% to 67%, and the number of patients whose surgical specimen had no living cancer cells at the time of surgery became almost 3 times higher. Serious side effects were similar in the two groups and surgery was not delayed. In the final analysis, overall survival also favoured durvalumab.

Key results

67.4% vs 58.5%

Two-year event-free survival

HR for event or death 0.71 (95% CI 0.58–0.86); P<0.001; median follow-up 31.5 months

75.7% vs 70.4%

Two-year overall survival (paper's analysis)

P=0.03, which did not cross the prespecified significance threshold (P<0.0001) at this analysis

HR 0.78

Overall survival (final analysis, FDA label)

95% CI 0.63–0.96; P=0.021; median not reached in either group

19.2% vs 7.2%

Pathological complete response

Relative risk 2.69 (95% CI 1.86–3.90)

71.6% vs 71.2%

Grade 3 or 4 adverse events

340 vs 334 patients

Drugs in this study:Docetaxel (Taxotere)Fluorouracil (5-FU)Oxaliplatin (Eloxatin)Durvalumab (Imfinzi)

Dose and schedule cards

Durvalumab + FLOT (MATTERHORN trial)

Resectable adenocarcinoma of the stomach or gastroesophageal junction, stage II to IVA (AJCC 8th edition), ECOG 0–1, no active autoimmune diseaseOn the page “Stomach cancer” · Localized resectable disease: perioperative and adjuvant therapy

Resectable adenocarcinoma of the stomach or gastroesophageal junction, stage II to IVA (AJCC 8th edition), ECOG 0–1, no active autoimmune disease

Drug	Dose	Route	Schedule
Before surgery: 2 cycles
Durvalumab	1500 mg (body weight less than 30 kg: 20 mg/kg)	IV	Day 1
FLOT	Standard FLOT doses (regimen above)	IV	Days 1 and 15
After surgery: 2 cycles
Durvalumab	1500 mg (body weight less than 30 kg: 20 mg/kg)	IV	Day 1
FLOT	Standard FLOT doses (regimen above)	IV	Days 1 and 15
Maintenance: up to 10 cycles
Durvalumab	1500 mg (body weight less than 30 kg: 20 mg/kg)	IV	Day 1

Cycle length: Every 28 days (FLOT every 14 days, i.e., days 1 and 15 of each cycle)
Duration: 2 cycles before surgery; after surgery, 2 cycles with FLOT followed by durvalumab monotherapy for up to 10 cycles (a maximum of 12 cycles in total after surgery)

Durvalumab dose and schedule from the FDA label; in the MATTERHORN trial, event-free survival and overall survival were improved. The doses of the individual FLOT components are not stated separately in the label or the abstracts; the standard FLOT4 doses serve as the basis.

On the page “Stomach cancer” · Localized resectable disease: perioperative and adjuvant therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Durvalumab + FLOT

Durvalumab 1500 mg IV on day 1 every 4 weeks, with FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) on days 1 and 15 of each four-week cycle, for 4 cycles (2 cycles before surgery and 2 cycles after surgery); then durvalumab 1500 mg alone every 4 weeks for up to 10 further cycles (a maximum of 12 cycles after surgery in total). According to the FDA label, for weight below 30 kg: 20 mg/kg.

The doses of the individual FLOT components are not stated in the abstract or the FDA label (standard FLOT doses in the FLOT4 trial: docetaxel 50, oxaliplatin 85, leucovorin 200 and fluorouracil 2600 mg/m² as a 24-hour infusion, every 2 weeks).

2Placebo + FLOT (control group)

Placebo on day 1 every 4 weeks with FLOT on days 1 and 15 of each four-week cycle for 4 cycles (2 cycles before and 2 cycles after surgery), then placebo every 4 weeks for up to 10 further cycles.

Source of the regimen details: Abstract of the paper (NEJM 2025: durvalumab 1500 mg every 4 weeks, 4 cycles of FLOT and then 10 cycles) and the FDA label for Imfinzi (sections 2.2 and 14.7: FLOT on days 1 and 15 of each 4-week cycle); the doses of the individual FLOT components are not stated in these sources

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with resectable, untreated gastric or gastro-oesophageal junction adenocarcinoma (per the FDA label: stage II to IVA by AJCC 8th edition), with WHO/ECOG performance status 0 or 1 and no prior exposure to immunotherapy; patients with active or documented history of autoimmune disease or immunosuppressive medication within 14 days before starting treatment were excluded.

Endpoints

Primary endpoint: event-free survival (EFS).

Secondary endpoints: including overall survival (OS) and pathological complete response (pCR).

Safety and side effects

Adverse events with a maximum grade of 3 or 4 were reported in 340 patients (71.6%) in the durvalumab group and 334 patients (71.2%) in the placebo group. Delay of surgery occurred in 10.1% and 10.8%, and delay in starting postoperative treatment in 2.3% and 4.6% of patients, respectively; that is, adding durvalumab did not interfere with timely surgery.

Clinical significance and place in guidelines

Based on MATTERHORN, in November 2025 the US Food and Drug Administration (FDA) approved durvalumab with FLOT as perioperative treatment, followed by single-agent durvalumab, for adults with resectable gastric or gastro-oesophageal junction adenocarcinoma. According to the FDA label, in the final overall survival analysis the HR for death was 0.78 (95% CI 0.63–0.96; P=0.021). This is the first FDA-approved perioperative immunotherapy regimen in gastric cancer. The ESMO 2022 and NCCN version 2.2025 guidelines were published before these results; the status of this regimen in newer guidelines should be checked in current versions.

Limitations

At the time of publication, the overall survival difference had not yet reached the very stringent significance threshold of the interim analysis (the final overall survival result was later reported in the FDA label). The role of PD-L1 expression and MSI status in the magnitude of benefit in subgroups needs further analysis. The study was sponsored by the manufacturer, and the value of durvalumab with other regimens (other than FLOT) or in patients undergoing upfront surgery has not been studied.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.