A significant advancement in the treatment landscape for resectable early-stage gastric and gastroesophageal junction (GEJ) cancers is on the horizon, following the FDA granting priority review and breakthrough therapy designation to durvalumab (Imfinzi).1 This decision underscores the potential for durvalumab to become the first and only perioperative immunotherapy-based regimen in this challenging setting, addressing a critical unmet medical need where disease recurrence remains common despite curative-intent surgery and chemotherapy.
The supplemental biologics license application (sBLA) for durvalumab is supported by compelling data from the phase 3 MATTERHORN trial (NCT04592913). Results from this global, randomized, double-blind, placebo-controlled study were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) for patients treated with the durvalumab-based perioperative regimen. Specifically, the regimen led to a 29% reduction in the risk of disease progression, recurrence, or death compared with chemotherapy alone (HR, 0.71; 95% CI, 0.58–0.86; P <.001).1,2
While the estimated median EFS had not yet been reached in the durvalumab arm at the time of the interim analysis, it stood at 32.8 months for the comparator arm, signaling a notable clinical benefit. The estimated EFS rates further highlighted this advantage, with 78.2% of patients in the durvalumab arm being event-free at 1 year compared with 74.0% in the comparator arm. At 24 months, these rates were 67.4% vs 58.5%, respectively, suggesting a growing magnitude of benefit over time. A strong trend favoring overall survival (OS) was also observed (HR, 0.78; 95% CI, 0.62–0.97; P =.025), with formal assessment of OS planned for the final analysis of the trial.
Gastric/GEJ tumor: ©LASZLO – stock.adobe.com
Gastric cancer, including GEJ cancer, represents a substantial global health burden, ranking as the fifth most common cancer worldwide and a leading cause of cancer mortality. In 2024, approximately 6500 patients in the US were treated for early-stage and locally advanced gastric or GEJ cancer.1 Despite aggressive treatment approaches involving curative surgery and perioperative chemotherapy, a significant proportion of patients experience disease recurrence within a year, and 5-year survival rates remain suboptimal, with less than half of patients surviving beyond 5 years. The need for more effective treatment strategies is paramount to improve long-term outcomes for these patients.
The MATTERHORN trial protocol involved a perioperative approach, where patients received durvalumab in combination with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy before surgery, followed by adjuvant durvalumab plus FLOT chemotherapy, and then durvalumab monotherapy after surgery. This comprehensive treatment strategy aims to leverage durvalumab’s mechanism of action as a human monoclonal antibody that binds to the PD-L1 protein, thereby blocking its interaction with PD-1 and CD80. This blockade is designed to counteract tumor immune evasion tactics and restore antitumor immune responses, offering a novel therapeutic avenue for a disease that has seen limited advancements in recent decades.
The safety profile observed in the MATTERHORN trial was consistent with the known profiles of durvalumab and FLOT chemotherapy, with similar rates of grade 3 or higher adverse events between the treatment and comparator arms. This manageable safety profile is crucial for a regimen intended for a broad patient population undergoing demanding perioperative treatment.1,2
Regulatory applications for durvalumab in this setting are also under review in the European Union, Japan, and several other countries, indicating a global effort to bring this potential new standard of care to patients worldwide.1 The anticipated FDA action date for the sBLA is in the fourth quarter of 2025, a timeline that underscores the urgency and significance placed on this potential approval by regulatory authorities and the oncology community. If approved, this perioperative durvalumab regimen could redefine the clinical paradigm for patients with resectable early-stage gastric and GEJ cancers, offering a much-needed improvement in the quest for durable remissions and extended survival.