Oncology Drug Approval News Flash：FDA approves durvalumab (Imfinzi) plus FLOT　as perioperative therapy for resectable gastric and GEJ adenocarcinoma

On November 25, 2025, the U.S. Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca) in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as neoadjuvant and adjuvant treatment, followed by single-agent durvalumab, for adults with resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC).

Eligible patients have previously untreated, resectable stage II–IVA GC/GEJC who are candidates for curative surgery.

MATTERHORN trial (NCT04592913)

Efficacy was evaluated in MATTERHORN, a randomized, double-blind, placebo-controlled, multicenter study enrolling 948 patients with previously untreated, resectable stage II–IVA GC/GEJC.

• Study design
  • Patients were randomized 1:1 to:
    1. Durvalumab + FLOT (neoadjuvant) → surgery → durvalumab + FLOT (adjuvant) → durvalumab monotherapy
    2. Placebo + FLOT (neoadjuvant) → surgery → placebo + FLOT (adjuvant)
• Endpoints
  • Primary: Event-free survival (EFS) by blinded independent central review
  • Key secondary: Overall survival (OS), pathological complete response (pCR) rate by blinded central pathology review

The trial was not designed to isolate the effect of durvalumab in each phase (neoadjuvant vs adjuvant).

Key efficacy results

• Event-free survival (EFS)
  • Durvalumab + FLOT: median not reached (NR) (95% CI: 40.7, not estimable [NE])
  • Placebo + FLOT: median 32.8 months (95% CI: 27.9, NE)
  • Hazard ratio (HR) 0.71 (95% CI: 0.58, 0.86); p < 0.001
• Overall survival (OS)
  • Median OS was NR in both arms
  • HR 0.78 (95% CI: 0.63, 0.96); p = 0.021
• Pathological complete response (pCR, central review)
  • Durvalumab + FLOT: 19.2% (95% CI: 15.7, 23.0)
  • Placebo + FLOT: 7.2% (95% CI: 5.0, 9.9)
  • p < 0.001

These findings indicate a clinically meaningful improvement in EFS and pCR, with an emerging OS benefit, for perioperative durvalumab plus FLOT compared with FLOT alone.

Safety and key warnings

The Imfinzi prescribing information includes warnings and precautions for:

• Immune-mediated adverse reactions
  • e.g., pneumonitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions
• Infusion-related reactions
• Complications of allogeneic hematopoietic stem cell transplantation
• Embryo-fetal toxicity

Clinicians should review the full prescribing information for detailed guidance on dosing modifications, treatment interruption/discontinuation, and monitoring.

Dosing regimen: perioperative durvalumab + FLOT

For patients weighing ≥30 kg, the recommended durvalumab dose is:

• 1,500 mg every 4 weeks in combination with chemotherapy for up to 4 cycles (neoadjuvant + adjuvant)
• Followed by 1,500 mg every 4 weeks as a single agent for up to 10 additional cycles (adjuvant)

For patients <30 kg, durvalumab is given at 20 mg/kg every 4 weeks with chemotherapy for up to 4 cycles and then 20 mg/kg every 4 weeks as a single agent for up to 10 cycles. Treatment continues until disease progression, recurrence, unacceptable toxicity, or completion of 12 postsurgical cycles.

Regulatory context: Project Orbis and expedited programs

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that enables concurrent submission and review of oncology drugs among international partners, including Australia’s TGA, Brazil’s ANVISA, Health Canada, Israel’s Ministry of Health, and Switzerland’s Swissmedic.

The application received:

• Priority review
• Breakthrough therapy designation
• Orphan drug designation

An Assessment Aid was submitted to facilitate the FDA’s evaluation.

Editorial perspective (Morningglorysciences)

Perioperative FLOT has emerged as a standard of care for resectable gastric and GEJ adenocarcinoma, but the incremental value of adding immunotherapy has remained an open question.

MATTERHORN now shows that adding durvalumab to FLOT can:

• Prolong EFS with a 29% relative risk reduction
• Increase pCR rates from ~7% to ~19%
• Provide early signals of OS benefit

These findings support a shift toward IO-enhanced perioperative strategies in fit patients with resectable GC/GEJC.

In real-world practice, however, FLOT is already a demanding regimen. Oncologists will need to balance:

• The intensity and duration of perioperative durvalumab + FLOT
• Tolerance in older or frail patients
• Long-term immune-related toxicities
• Economic and access considerations across different healthcare systems

Overall, this approval further strengthens the role of immunotherapy across the continuum of treatment in upper GI cancers and may reshape multidisciplinary decision-making around surgery and systemic therapy in resectable disease.

This article was produced by the Morningglorysciences Editorial Team.

Related Articles

Oncology FDA Approval Archive