Durvalumab Approved For Resectable Upper Gastrointestinal Cancers
Key Points
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The FDA approved durvalumab plus FLOT for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma based on the MATTERHORN trial.
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Compared with placebo, durvalumab showed an improvement in overall survival (OS), and improved event-free survival (EFS) regardless of PD-L1 expression or nodal involvement.
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Durvalumab is well tolerated, and modifying the FLOT regimen may help manage toxicity concerns for typical patients with gastric or GEJ cancers.
Durvalumab For Gastric or GEJ Adenocarcinoma
Based on the MATTERHORN trial, the FDA approved perioperative durvalumab plus FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) for patients with resectable gastric or GEJ adenocarcinoma. Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with the lead author on MATTERHORN, Yelena Janjigian, MD, of Memorial Sloan Kettering Cancer Center, to discuss the trial and its impact for community medical oncologists.
MATTERHORN Data Updates
The phase 3 MATTERHORN trial evaluated durvalumab or placebo plus FLOT for 4 cycles (2 neoadjuvant and 2 adjuvant), followed by durvalumab or placebo every 4 weeks for 10 cycles. The durvalumab and placebo arms each contained 474 patients with previously untreated, localized non-metastatic, gastric or GEJ adenocarcinoma.
In the initial publication in the New England Journal of Medicine, the 2-year EFS was 67.4% in the durvalumab group versus 58.5% in the placebo group (hazard ratio [HR] for events or death, 0.71; 95% CI, 0.58-0.86; P < .001) over a median follow-up of 31.5 months (interquartile range, 26.7-36.6).
The 2-year OS was 75.7% with durvalumab versus 70.4% with placebo (months 0-12 HR for death, 0.99; 95% CI, 0.70-1.39; month 12 onward HR for death, 0.67; 95% CI, 0.50-0.90; P = .03). Overall, 19.2% of patients in the durvalumab group achieved a pathological complete response (pCR) versus 7.2% in the placebo group (relative risk, 2.69; 95% CI, 1.86-3.90).
In the final OS analysis presented at the European Society of Medical Oncology (ESMO) Congress 2025, durvalumab plus FLOT significantly improved OS compared with placebo plus FLOT (HR, 0.78; 95% CI, 0.63-0.96; P = .021). This benefit was seen regardless of PD-L1 tumor area positivity status.
Among patients with evaluable surgical samples, the rate of no nodal involvement was higher in the durvalumab arm versus the placebo arm (58.2% vs 44.8%; odds ratio, 1.72; 95% CI, 1.30-2.27). Compared with placebo, the addition of durvalumab improved EFS for patients with a pCR (HR, 0.29; 95% CI, 0.08-0.96), a major pathological response (HR, 0.32; 95% CI, 0.15-0.68), or any pathological response (HR, 0.60; 95% CI, 0.46-0.79), regardless of negative nodal involvement (HR, 0.74; 95% CI, 0.46-1.18) or positive nodal involvement (HR, 0.77; 95% CI, 0.58-1.02).
Key Durvalumab Takeaways
Most gastric and GEJ adenocarcinomas are PD-L1 positive. However, MATTERHORN data suggest durvalumab improved survival even for patients with 0% PD-L1 expression, and oncologists should not restrict durvalumab use based on PD-L1 status, said Dr. Janjigian.
In other cancers with similar approved immunotherapy-based perioperative regimens,, researchers are exploring the prospect of stopping the single-agent adjuvant immunotherapy component based on circulating tumor DNA (ctDNA) or other biomarkers. However, available data have only shown ctDNA to be a prognostic biomarker and not a predictive one. “Would I change practice based on ctDNA, no,” said Dr. Janjigian. “I think going by patients’ ability to tolerate adjuvant therapy, or deescalation based on what the patient is doing, is really the gold standard.”
Generally, durvalumab is well tolerated, and most toxicity experienced by patients is related to chemotherapy. For typical patients with gastric or GEJ cancer who are older or malnourished, starting with a reduced FLOT dose or modifying the regimen may be appropriate. Dr. Janjigian said she often omits leucovorin or reduces the dose of oxaliplatin or docetaxel if adverse events or nutrition are a concern.