The Matterhorn Trial, a landmark phase III study published in the New England Journal of Medicine, evaluates durvalumab, an anti-PD-L1 monoclonal antibody, combined with FLOT chemotherapy in resectable gastric and gastroesophageal junction (GEJ) cancer. Consequently, this global, double-blind, placebo-controlled trial demonstrates significant improvements in event-free survival (EFS). For oncologists and cancer researchers, these findings address critical gaps in understanding immunotherapy’s role in gastric cancer management. Therefore, this article synthesizes the trial’s design, results, and implications, complemented by a concise OncologyTube video summary.
Matterhorn Trial Design and Patient Population
The Matterhorn Trial (NCT04592913) enrolled 948 patients with resectable gastric or GEJ adenocarcinoma (T2–4NanyM0 or T1N+M0). Specifically, patients were randomized 1:1 to two arms. In the durvalumab arm, patients received durvalumab (1500 mg IV every 4 weeks) plus FLOT (docetaxel 50 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², fluorouracil 2600 mg/m² every 2 weeks) for 2 neoadjuvant and 2 adjuvant cycles, followed by durvalumab monotherapy for 10 cycles. In contrast, the placebo arm received placebo plus FLOT, followed by placebo for 10 cycles. Moreover, stratification by geographic region, lymph node status, and PD-L1 expression ensured methodological rigor.
Primary and Secondary Endpoint Results
The trial’s primary endpoint, EFS, showed significant improvement with durvalumab. For instance:
- EFS at 24 Months: 67% (durvalumab) vs. 59% (placebo).
- Hazard Ratio: 0.71 (95% CI 0.58–0.86, P < 0.001).
- Median EFS: Not reached (durvalumab) vs. 32.8 months (placebo).
Furthermore, secondary endpoints reinforced durvalumab’s efficacy:
- Pathological Complete Response (pCR): 19% (durvalumab) vs. 7% (placebo), odds ratio 3.08 (P < 0.00001).
- R0 Resection Rates: 88% (durvalumab) vs. 84% (placebo).
- Overall Survival (OS): Immature, with a hazard ratio of 0.82 (95% CI 0.63–1.06).
As a result, these data highlight durvalumab’s potential to enhance clinical outcomes in gastric and GEJ cancer.
Biomarker Insights
Notably, the trial demonstrated EFS benefits across PD-L1 expression levels (≥1% vs. <1%) and microsatellite instability (MSI) status (MSI-H vs. non-MSI-H). In particular, MSI-H patients exhibited higher pCR rates, suggesting MSI status as a predictive biomarker. Consequently, PD-L1 Combined Positive Score (CPS) analysis provides critical data for researchers developing personalized treatment strategies in gastric cancer.
Safety and Tolerability Profile
The safety profile of durvalumab plus FLOT was manageable and consistent with prior studies. Specifically:
- Grade 3–4 Adverse Events (AEs): 68% (durvalumab) vs. 65% (placebo).
- Common AEs: Neutropenia (39%), nausea (22%), fatigue (19%).
- Immune-Mediated AEs (irAEs): 15% (durvalumab) vs. 5% (placebo), predominantly Grade 1–2, including hepatitis, colitis, and endocrinopathies.
- Surgical Complications: No increase observed with durvalumab, confirming perioperative safety.
Thus, these findings guide clinicians in managing AEs, particularly neutropenia and irAEs, using established protocols.
Implications for Oncology Practice
As the first trial to demonstrate EFS benefits with immunotherapy in resectable gastric and GEJ cancer, the Matterhorn Trial challenges the FLOT-only standard of care. Therefore, oncologists may consider durvalumab plus FLOT as a new treatment paradigm, particularly for PD-L1-positive or MSI-H patients. Additionally, hematologists can leverage neutropenia data to optimize supportive care strategies. Meanwhile, researchers gain valuable insights into PD-L1 and MSI-H biomarkers, supporting further investigation into combination therapies, such as durvalumab with tremelimumab or zolbetuximab for CLDN18.2-positive tumors.
Future Directions
Looking ahead, ongoing analyses will provide updated OS data and deeper biomarker correlations. For example, presentations at ASCO and ESMO will offer further insights into durvalumab’s efficacy across gastric cancer subtypes. Moreover, researchers are encouraged to explore durvalumab’s role in unresectable or metastatic settings and its synergy with other checkpoint inhibitors.
Resources for Clinicians and Researchers
- ClinicalTrials.gov: Access the Matterhorn Trial protocol (NCT04592913).
- NEJM Publication: Review detailed trial methodology and results.
- OncologyTube Video: Watch a visual summary of the trial’s key findings.
Conclusion
In summary, the Matterhorn Trial establishes durvalumab plus FLOT as a transformative approach for resectable gastric and GEJ cancer, significantly improving EFS and pCR rates. Consequently, these findings provide oncologists and researchers with robust data to advance clinical practice and personalized treatment strategies. Explore the OncologyTube video and share your insights to stay at the forefront of gastric cancer research.
References
- Janjigian YY, et al. Durvalumab plus FLOT in resectable gastric and gastroesophageal junction cancer. N Engl J Med. 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2503701
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