The phase 3 MATTERHORN trial demonstrated that adding durvalumab to perioperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy significantly improved overall survival (OS) compared with placebo plus FLOT in patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma, with benefits observed regardless of PD-L1 status. 

Earlier analyses from this trial had shown gains in event-free survival (EFS), pathologic complete response (pCR), and major pathologic response (MPR). This final analysis presented at the 2025 ESMO Congress by Josep Tabernero, MD, PhD, Vall d’Hebron University Hospital, Barcelona, Spain, confirmed the durability and clinical significance of these outcomes and reports on final OS.

This global, double-blind, randomized phase 3 study, assigned patients 1:1 to receive durvalumab 1500 mg or placebo every 4 weeks (Q4W) plus FLOT every 2 weeks on days 1 and 15 for 4 cycles (2 neoadjuvant and 2 adjuvant) followed by durvalumab or placebo Q4W for 10 additional cycles. OS, defined as time from randomization to death from any cause, was evaluated in all randomized patients and by PD-L1 tumor area positivity (TAP) subgroups (<1% and ≥1%). EFS, defined as time to progression, recurrence, or death, was assessed by pathologic response (pCR, MPR, any pathologic response [pR]) and nodal status (ypN).

Durvalumab plus FLOT demonstrated a statistically significant improvement in OS compared with placebo plus FLOT (hazard ratio [HR], 0.78; 95% CI, 0.63 to 0.96; P = .021). OS improvement was consistent across PD-L1 expression levels, including TAP <1% (HR, 0.79; 95% CI, 0.41 to 1.50) and TAP ≥1% (HR, 0.79; 95% CI, 0.63 to 0.99). Among patients with evaluable surgical samples, the rate of ypN-negative disease was higher with durvalumab (58.2%) than with placebo (44.8%), corresponding to an odds ratio of 1.72 (95% CI, 1.30 to 2.27).

EFS was improved with durvalumab plus FLOT in patients achieving a pCR (HR, 0.29; 95% CI, 0.08 to 0.96), MPR (HR, 0.32; 95% CI, 0.15 to 0.68), or any pR (HR, 0.60; 95% CI, 0.46 to 0.79), with benefits maintained regardless of nodal status (ypN-negative HR, 0.74; 95% CI, 0.46 to 1.18; ypN-positive HR, 0.77; 95% CI, 0.58 to 1.02).

These results confirm that perioperative durvalumab combined with FLOT not only extends survival but also enhances pathologic and event-free outcomes compared with FLOT alone. The consistency of benefit across PD-L1 subgroups and pathologic response categories supports durvalumab plus FLOT as a new standard of care for resectable gastric and GEJ adenocarcinoma.

Source:

Tabernero J, Al-Batran S, Wainberg ZA, et al. 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 the 2025 ESMO Congress; October 17-21, 2025. Berlin, Germany. LBA81