Durvalumab Plus Chemotherapy Sets New Standard in Resectable Gastric and GEJ Cancer

Durvalumab (Imfinzi, AstraZeneca) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) yielded clinically meaningful improvements in survival—irrespective of PD-L1 status—in patients with resectable gastric and gastroesophageal junction (GC/GEJ) cancer. The data, presented at the European Society of Medical Oncology 2025 Congress, are from the global, phase 3 MATTERHORN trial (NCT04592913).

What Is GEJ Cancer?

Gastric cancer is the fifth most common cancer worldwide but is relatively rare in the United States, accounting for 1% of all cancer diagnoses. GEJ is an aggressive, challenging, and rare cancer that begins at the junction of the esophagus and the stomach. Due to GEJ’s less common status, causal factors for the disease are largely unknown.¹

Some studies suggest genetics, the environment, and lifestyle habits—such as diet, alcohol/tobacco consumption, low physical activity, and age—which are known drivers of various oncologic and nononcologic diseases. Other contributing factors may include history with gastroesophageal reflux disease (GERD; Barrett’s esophagus) or Helicobacter pylori (H. pylori).^2,3

Due to its rarity, GEJ symptoms are difficult to diagnose, and many patients experience the onset of symptoms when the disease is in later stages or spreads. Symptoms include weight loss, vomiting, blood in the stool, leading to anemia and fatigue, and various digestive issues, including chest pain, heartburn, or difficulty swallowing.^2,3

Given that these symptoms overlap with those of numerous other gastrointestinal disorders, GEJ can be mistaken for more common gastrointestinal conditions such as GERD or peptic ulcer disease, delaying accurate diagnosis and timely treatment.

Treatment of GEJ is dependent on the disease stage. Stage 1 and 2 GEJ are typically treated via resection, but immunotherapy may also be an option. Standard of care for patients with locally advanced, unresectable disease can include chemotherapy, chemoradiation, radiation, or endoscopic treatments. Immunotherapy may also be used at this stage. However, patients who whose disease spreads to other parts of the body receive immunotherapy, which is typically combined with chemotherapy and targeted treatments.^2,3

What Is Durvalumab?

Durvalumab is a PD-L1 inhibitor first approved by the FDA for adults with limited-stage small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. In 2025, durvalumab received a second approval with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent durvalumab as adjuvant treatment following radical cystectomy, for adults with muscle invasive bladder cancer.^4,5

In the MATTERHORN trial, durvalumab plus FLOT demonstrated statistically significant benefits improved event-free survival (EFS), pathological complete response (pCR) rate and major pathological response (MPR) rate in participants with resectable GC/GEJ adenocarcinoma.

What Does the Study Show?

The global, double-blind, phase 3 study, randomized patients 1:1 to either 1500 mg of durvalumab or placebo every 4 weeks (Q4W) on day 1 plus FLOT every 2 weeks on days 1 and 15 for 4 cycles (2 cycles neoadjuvant / 2 cycles adjuvant). This was followed by 1500 mg or placebo on day 1 Q4W for 10 additional cycles.⁶

Overall survival (OS; time from randomization to death) was assessed in all randomized patients and stratified by PD-L1 status (Tumor Area Positivity [TAP] <1% vs ≥1%). EFS (time from randomization to disease progression, local or distant recurrence, or death), determined per RECIST v1.1 by blinded independent central review and/or local pathology assessment.⁶

Durvalumab in combination with FLOT showed clinically meaningful improvements in OS compared with placebo (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63–0.96; P = 0.021). OS improved in patients with PD-L1 TAP less than 1% (HR, 0.79; 95% CI, 0.41–1.50) and TAP greater than or equal to 1% (HR, 0.79; 95% CI, 0.63–0.99).⁶

Among patients with evaluable surgical samples, the durvalumab plus FLOT regimen resulted in a higher rate of ypN– status compared with placebo and FLOT (58.2% vs 44.8%; odds ratio, 1.72; 95% CI, 1.30–2.27). EFS was improved with durvalumab versus placebo among patients who achieved a pathological response—including pCR and major pathological response—regardless of ypN status.⁶

"Any degree of pathological response was associated with improved overall survival for patients receiving anti-PD-1,” explained Josep Tabernero, MD, PhD, head of the Medical Oncology Department at Vall d'Hebron University Hospital, professor of Medicine at the Universitat de Vic, and director of the Vall d'Hebron Institute of Oncology in Barcelona, Spain.⁶

The findings from MATTERHORN underscore the potential of incorporating immunotherapy into perioperative treatment for gastric and gastroesophageal junction cancer. By demonstrating consistent survival benefits across PD-L1 subgroups and a higher rate of nodal clearance, durvalumab plus FLOT strengthens the rationale for immunotherapy in resectable disease—an area previously dominated by chemotherapy alone.⁶

“The overall survival results of the MATTERHORN study strongly support the use of perioperative durvalumab plus chemotherapy with FLOT as a new global standard of care for patients with localized [GC/GEJ],” Tabernero concluded.⁶

REFERENCES

1. Gastric and gastroesophageal junction cancers in focus: understanding potential symptoms, risks, and treatment options. AstraZeneca. July 8, 2025. Accessed October 17, 2025. https://www.astrazeneca-us.com/media/astrazeneca-us-blog/2025/gastric-and-gastroesophageal-junction…

2. Key statistics for esophageal cancer. American Cancer Society. August 14, 2025. Accessed October 17, 2025. https://www.cancer.org/cancer/types/esophagus-cancer/key-statistics.html

3. Treating Esophageal Cancer. American Cancer Society. August 14, 2025. Accessed October 17, 2025. https://www.cancer.org/cancer/types/esophagus-cancer/treating.html

4. FDA approves durvalumab for limited-stage small cell lung cancer. FDA. December 4, 2024. Accessed October 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-limited-stag…

5. FDA approves durvalumab for muscle invasive bladder cancer. FDA. March 28, 2025. Accessed October 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invas…

6. Tabernero J, Al-Batran S, Wainberg A.A, et al. LBA81 - 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: European Society of Clinical Oncology 2025 Congress. October 17, 2025, to October 21, 2025. Abstract LBA81