First Overall Survival Benefit With Durvalumab Plus FLOT in Early-Stage Gastric Cancer

The study demonstrated, for the first time, that perioperative immunotherapy, before and after surgery, prolongs patients' overall survival (OS) .

Adding durvalumab also significantly increased complete tumor disappearance before surgery, or pathological complete response (pCR) , from approximately 7% to 19% , representing an approximately 2.7-fold improvement .

These results make Durvalumab + FLOT a new standard-of-care candidate in early-stage gastric cancer.

Study Design

• Phase 3, double-blind, multicenter; Durvalumab + FLOT vs Placebo + FLOT.
• Perioperative sequence: 2 neoadjuvant cycles → surgery → 2 adjuvant cycles → 10 maintenance cycles (durvalumab/placebo).
• Main endpoints: EFS (event-free survival) and OS; secondary: pCR, MPR, pathological responses and nodal downstaging (ypN).

ASCO25 (Plenary + NEJM): Positive EFS & pCR

• EFS: HR 0.71 (0.58–0.86), 29% risk reduction.
• pCR: 19.2% vs 7.2% → RR 2.69 (1.86–3.90), ~2.7-fold increase.
• OS: Immature; HR 0.67, p=0.03 (formal threshold not crossed).

Clinical meaning: Delayed recurrence/progression, with potential to increase cure rates.

ESMO25 LBA81: Final OS and Detailed Pathology

• Overall OS: HR 0.78 (0.63–0.96), p=0.021 ✅
• PD-L1 (TAP) subgroups: TAP <1% HR 0.79 (0.41–1.50) — NS; TAP ≥1% HR 0.79 (0.63–0.99) — borderline. Interpretation: Benefit trend independent of PD-L1.
• Pathological responses (HR, associated with EFS contribution): pCR 0.29 (0.08–0.96) ✅; MPR 0.32 (0.15–0.68) ✅; Any pR 0.60 (0.46–0.79) ✅.
• Nodal downstaging: ypN– 58.2% vs 44.8%; OR 1.72 (1.30–2.27).
• ypN–/ypN+ and EFS: ypN– HR 0.74 (0.46–1.18) NS; ypN+ HR 0.77 (0.58–1.02) NS.

ASCO25 vs ESMO25—What Was Added?

Clinical Implications

• A new standard candidate: Perioperative Durvalumab + FLOTnow has EFS + OS positive results together.
• Biomarker: PD-L1-based selection is not mandatory, although the TAP ≥1% subgroup's CI reaches borderline significance— potentially useful for selection at some centers.
• Consistency with pathology: pCR/MPR gains biologically support long-term benefit.
• Surgical compatibility: Previous reports showed no major delay or toxicity increase; the clinical sequence can be maintained.

How Might We Apply It?

1. Patient selection: Stage II–IVA, resectable, ECOG 0–1; for subtypes such as MSI-H, EBV+, or HER2+, consider additional strategies through a tumor board decision.
2. Timing: 2 neoadjuvant cycles → surgery → 2 adjuvant cycles → 10 durvalumab maintenance cycles, with established team/logistics.
3. Pathology–radiology integration: pCR/MPR reporting according to Modified Ryan scoring, with clear nodal status.
4. Post-treatment monitoring: Integrate MRD/ctDNA programs, where available, for recurrence-risk stratification.

Commentary

MATTERHORN turning OS positive shows perioperative IO has crossed a barrier in this setting. Next steps include: MRD/ctDNA-guided treatment duration, molecular subtype -based personalization, and real-world data integration. Regional reimbursement and access will require health-economic models.

Source

Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. N Engl J Med. 2025. DOI: 10.1056/NEJMoa2503701.