MATTERHORN Trial at ASCO 2025: Durvalumab plus FLOT Shows Significant Improvement of EFS in Resectable Gastric and GEJ Cancer Treatment

At ASCO 2025 Plennary Session,  MATTERHORN trial results were presented by Dr. Yelena Janjigian, from MSK, demonstrating a statistically significant improvement in event-free survival (EFS) with durvalumab plus FLOT chemotherapy compared to FLOT alone in patients with resectable gastric and gastroesophageal junction cancer (GC/GEJC). These findings mark a major advancement in the perioperative treatment landscape, suggesting a potential shift in the global standard of care.

Background

Gastric and gastroesophageal junction adenocarcinomas remain aggressive malignancies, with high recurrence rates even after curative-intent surgery. The current perioperative standard of care, FLOT (5-fluorouracil, leucovorin, oxaliplatin, docetaxel), has improved outcomes, yet many patients relapse due to micrometastatic disease. Immune checkpoint inhibitors, particularly PD-1/PD-L1 inhibitors, have shown efficacy in the metastatic setting and are approved in combination with chemotherapy for advanced GC/GEJC. However, their role in the perioperative context remained undefined—until the MATTERHORN trial.

The MATTERHORN trial is investigating the addition of durvalumab, an anti-PD-L1 antibody, to FLOT in patients with resectable, locally advanced GC/GEJC. A previous report from the trial revealed a significant improvement in pathologic complete response (pCR) with the durvalumab-based regimen. The new interim analysis presented at ASCO 2025 builds on this foundation by reporting EFS as the primary endpoint.

Study Design

The MATTERHORN trial was a global, randomized, phase 3, double-blind study enrolling 948 patients with resectable, previously untreated, histologically confirmed gastric or gastroesophageal junction adenocarcinoma (Stage II–IVa, per AJCC 8th edition). Patients were randomly assigned in a 1:1 ratio to receive either durvalumab or placebo in combination with perioperative FLOT chemotherapy.

• Arm A: Durvalumab 1500 mg every 4 weeks + FLOT for 4 cyclesD1 and D15 q4w (2 neoadjuvant, 2 adjuvant) → durvalumab maintenance for 10 additional cycles
• Arm B: Placebo + FLOT → placebo maintenance

Patients were stratified by geographic region (Asia vs non-Asia), clinical lymph node status (positive vs negative), and PD-L1 tumor area positivity (≥1% vs <1%). The primary endpoint was event-free survival (EFS). Key secondary endpoints included pathologic complete response (pCR), overall survival (OS), and safety.

Methods

Patients aged ≥18 years were enrolled and underwent perioperative therapy as outlined. EFS was defined as the time from randomization to disease progression, local/distant recurrence, or death. Efficacy was assessed using RECIST v1.1 criteria, with events adjudicated by blinded independent central review and pathology. The statistical threshold for significance was set at p<0.0239 for this interim analysis.

Results

With a median follow-up of 31.5 months, the MATTERHORN trial met its endpoint with demonstrated statistically significant improvement in EFS:

mEFS in MATTERHORN Trial

• Not reached in durvalumab + FLOT arm (95% CI: 40.7–NR)
• 32.8 months with placebo + FLOT (95% CI: 27.9–NR)
• HR: 0.71 (95% CI: 0.58–0.86), p<0.001

EFS rates

• At 12 months: 78.2% (D + FLOT) vs 74.0% (P + FLOT)
• At 24 months: 67.4% vs 58.5%

Overall survival (interim)

• Median OS not reached in D + FLOT vs 47.2 months in P + FLOT
• HR: 0.78 (95% CI: 0.62–0.97), p=0.025 (OS data 33.9% mature)

Grade 3–4 adverse event rates were comparable between arms. Importantly, durvalumab did not delay surgical resection or initiation of adjuvant therapy.

Key Takeaways

• The MATTERHORN trial is the first global phase 3 study to show a clear EFS benefit with immunotherapy in the perioperative setting for resectable GC/GEJC.
• Durvalumab plus FLOT significantly reduced the risk of recurrence or progression compared to standard FLOT alone.
• OS data are still maturing but show a favorable trend in the immunotherapy arm.
• Safety profile was acceptable, with no new signals or impact on surgical timing.

These data support durvalumab + FLOT as a potential new global standard of care in resectable gastric and gastroesophageal junction adenocarcinoma. With its robust design, global applicability, and clinically meaningful outcomes, the MATTERHORN trial sets a new benchmark for the integration of immunotherapy into early-stage gastric cancer care.

You can Read the Full Article in NEJM

Summary by Amalya Sargsyan, MD