FDA Approves Durvalumab Plus FLOT in Early Stage Gastric/GEJ Cancers

The FDA has approved durvalumab (Imfinzi) plus fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for the treatment of patients with resectable, early-stage and locally advanced gastric and gastroesophageal junction (GEJ) cancers.¹

This approval is supported by data from the phase 3 MATTERHORN trial (NCT04592913). Data for event-free survival (EFS) were first presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.² At a median follow-up of 31.6 months (range, 0.0–48.1) for the durvalumab arm (n = 474) and 31.4 months (range, 0.0–48.1) for the placebo arm (n = 474), durvalumab plus FLOT generated a median EFS that was not reached (NR; 95% CI, 40.7–NR) compared with 32.8 months (95% CI, 27.9–NR) for placebo plus FLOT (HR, 0.71; 95% CI, 0.58–0.86; P <.001). In the durvalumab arm, the 18- and 24-month EFS rates were 73% and 67%, respectively. These respective rates were 64% and 59% in the placebo arm.

Overall survival (OS) data were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.³ Here, with a data cutoff date of September 1, 2025, the final OS analysis of the intention-to-treat population demonstrated an HR of 0.78 (95% CI, 0.63–0.96; P =.021) in theinvestigational arm vs the control arm, with median OS not reached in either arm. 

Additionally, a survival analysis stratified by demographic and clinical characteristics demonstrated thatOS improvement was consistent across most key subgroups. A similar improvement in OS was achieved regardless of PD-L1 status. Among patients who were PD-L1–positive (PD-L1 TAP ≥1%), the HR was 0.79 (95% CI, 0.63–0.99), while the HR was 0.79 (95% CI, 0.41–1.50) in patients who were PD-L1–negative (PD-L1 TAP <1%), even demonstrating identical HRs across groups. 

The MATTERHORN trial protocol involved a perioperative approach, where patients received durvalumab in combination with FLOT chemotherapy before surgery, followed by adjuvant durvalumab plus FLOT chemotherapy, and then durvalumab monotherapy after surgery. This comprehensive treatment strategy aimed 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.²

The application for durvalumab was granted priority review and breakthrough therapy designation in July 2025.⁴

REFERENCES:

1. FDA approves durvalumab for resectable gastric or gastroesophageal junction adenocarcinoma. News release. US FDA. Published online and accessed November 25, 2025. https://tinyurl.com/mvaftssb

2. Janjigian Y, Al-Batran S-E, Wainberg Z, et al. Event-free survival (EFS) in MATTERHORN: a randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2025;43(suppl 17):LBA5. doi:10.1200/JCO.2025.43.17_suppl.LBA5

3. Tabernero J. Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Presented at: ESMO 2025 Congress; October 17–20, 2025; Berlin, Germany. Abstract LBA81.

4. IMFINZI® (durvalumab) granted Priority Review and Breakthrough Therapy Designation in the US for patients with resectable early-stage gastric and gastroesophageal junction cancers. News release. AstraZeneca. July 28, 2025. Accessed October 23, 2025. https://tinyurl.com/yfczjf3h