Perioperative Durvalumab Plus FLOT Improves Survival in Resectable Gastric and GEJ Cancer

The FDA has approved AstraZeneca’s Imfinzi (durvalumab) in combination with FLOT chemotherapy as the first and only perioperative immunotherapy for patients with resectable, early-stage and locally advanced gastric and gastroesophageal junction (GEJ) cancers. Approval is based on the Phase III MATTERHORN trial, which demonstrated a 29% reduction in risk of progression, recurrence, or death and a 22% reduction in risk of death compared with chemotherapy alone, establishing a new perioperative standard of care in a curative-intent setting.

Clinical Takeaway

In the MATTERHORN trial, perioperative durvalumab plus FLOT significantly improved event-free survival (EFS) and overall survival (OS) versus chemotherapy alone in patients with resectable Stage II–IVA gastric and GEJ cancers. At 24 months, EFS was 67.4% versus 58.5% in the control arm, with the survival benefit increasing over time. Benefits were observed regardless of PD-L1 status, without compromising surgical feasibility or increasing high-grade toxicity, supporting this regimen as a new curative-intent treatment paradigm.

Drug Profile & Mechanism

• Agent: durvalumab (Imfinzi) + FLOT chemotherapy
• Class: Human Monoclonal Antibody + combination treatment (fluorouracil + leucovorin + oxaliplatin + docetaxel)
• Mechanism of action:
  • durvalumab blocks PD-L1, restoring anti-tumor T-cell activity
  • FLOT chemotherapy disrupts DNA synthesis, DNA integrity, and cell division
• Route of administration:
  • intravenous (durvalumab and FLOT)
• Target population: Adult patients with resectable, early-stage or locally advanced (Stages II–IVA) gastric and GEJ cancers

MATTERHORN Phase III trial Study Design (NCT04592913)

• Study Type: Global, Interventional (treatment), randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial
• Population: 957
• Comparator: placebo + FLOT
• Treatment Regimen: durvalumab + FLOT
• Follow Up Duration: 31.5 months
• Key Endpoints:
  • Primary: Event-Free-Survival (EFS)
  • Secondary: Pathologic complete response (pCR) ,Overall survival (OS)

Efficacy Outcomes

• Primary Endpoint Results: (2 year EFS)
  • Durvalumab + FLOT: 67.4%
  • Placebo + FLOT: 58.5%
  • Hazard ratio (EFS): 0.71 (95% CI, 0.58–0.86; P<0.001)
• Secondary Endpoint Results:
  • Two-year OS:
    • Durvalumab + FLOT: 75.7%
    • Placebo + FLOT: 70.4%
• pCR Rate:
  • durvalumab + FLOT: 19.2%
  • placebo + FLOT: 7.2%

Regulatory Milestones

• Approval Date: November 25, 2025
• Regulatory Pathway:
  • Priority Review
  • Project Orbis (concurrent international review with Australia, Canada, and Switzerland)
• Approval Review:
  • Approved by the US Food and Drug Administration (FDA) based on event-free survival (primary endpoint) and overall survival data from the MATTERHORN Phase III trial

Safety

• Overall AE Burden: Overall manageable, with no added high-grade toxicity and no impact on surgery completion.
• Grade ≥3 Events:
  • Durvalumab + FLOT: 71.6%
  • Placebo + FLOT: 71.2%
• Delayed Surgery:
  • Durvalumab + FLOT: 10.1%
  • Placebo + FLOT: 10.8%
• Delayed Adjuvant Treatment:
  • durvalumab + FLOT: 2.3%
  • placebo + FLOT: 4.6%
• Treatment-related deaths: Comparable between arms; largely chemotherapy-driven
  • durvalumab + FLOT: 30.6%
  • placebo + FLOT: 37.1%
• Notable toxicity patterns:
  • Toxicity burden remained chemotherapy-driven, not immunotherapy-driven

Key Clinical Implications

✔ Establishes the first perioperative immunotherapy standard for resectable gastric and GEJ cancers.

✔ Significantly reduces recurrence and mortality risk versus chemotherapy alone.

✔Shows durable, time-dependent survival benefit on long-term follow-up.

✔Effective regardless of PD-L1 status, simplifying patient selection.

✔Maintains surgical safety and feasibility without added high-grade toxicity.

Bottom Line

This study establishes the first FDA-approved perioperative immunotherapy for resectable gastric and GEJ cancers, showing meaningful and durable survival benefits without added surgical risk. It simplifies clinical decision-making by providing effective treatment regardless of PD-L1 status and integrating safely into existing chemotherapy-surgery pathways.

Sources:

• AstraZeneca. (2025, November 25). IMFINZI approved in the US as first and only perioperative immunotherapy for patients with early gastric and gastroesophageal cancers. AstraZeneca. Retrieved from https://www.astrazeneca.com/media-centre/press-releases/2025/imfinzi-approved-in-the-us-as-first-and-only-perioperative-immunotherapy-for-patients-with-early-gastric-and-gastroesophageal-cancers.html
• Janjigian, Y. Y., Al-Batran, S. E., Wainberg, Z. A., et al. (2025). Perioperative durvalumab in gastric and gastroesophageal junction cancer. New England Journal of Medicine, 393(3), 217–230. https://doi.org/10.1056/NEJMoa2503701
• National Library of Medicine. (n.d.). Assessing durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer (MATTERHORN) (NCT04592913). ClinicalTrials.gov. Retrieved December 24, 2025, from https://clinicaltrials.gov/study/NCT04592913
• OncoDaily. (2025, October 17). MATTERHORN Trial at ESMO 2025: Durvalumab plus FLOT in resectable gastric and GEJ adenocarcinoma. OncoDaily. https://oncodaily.com/oncolibrary/matterhorn-trial-durva-plus-flot-esmo25