MATTERHORN: Durvalumab plus FLOT significantly improves event-free survival in resectable gastric/GEJ adenocarcinoma

A new standard may be emerging for the perioperative treatment of resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. Results from the phase 3 multinational, double-blind, randomised MATTERHORN trial showed that adding the programmed cell death-ligand 1(PD-L1) inhibitor durvalumab to the standard FLOT regimen significantly improves event-free survival (EFS) in this high-risk population, without increasing toxicity or compromising surgical feasibility.

Dr Yelena Janjigian (Memorial Sloan Kettering Cancer Center, NY, USA) presented the late-breaking results of the MATTERHORN study (NCT04592913), which were simultaneously published in the New England Journal of Medicine [1,2].

A total of 948 participants with resectable gastric or GEJ adenocarcinoma were enrolled and randomised 1:1 to receive either durvalumab (1,500 mg every 4 weeks) or placebo, combined with 4 cycles of perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel; 2 neoadjuvant and 2 adjuvant), followed by 10 additional cycles of durvalumab or placebo monotherapy. The primary endpoint was EFS, and the secondary endpoints included overall survival (OS) and pathological complete response (pCR).

After a median follow-up of 31.5 months, the trial met its primary endpoint with a statistically significant improvement in EFS. At 2 years, the EFS rate was 67.4% in the durvalumab group compared with 58.5% in the placebo group (HR 0.71; 95% CI 0.58–0.86; P<0.001). Durvalumab also improved pCR rates, with 19.2% of participants achieving pCR versus just 7.2% in the placebo group (relative risk 2.69; 95% CI 1.86–3.90), suggesting enhanced tumour eradication in the neoadjuvant setting. The OS analysis also favoured durvalumab, particularly beyond the first year of treatment. For the durvalumab arm, the 2-year OS rate was 75.7% compared to 70.4% with placebo. Piecewise analysis revealed an HR of 0.99 (95% CI 0.70–1.39) in the first 12 months and 0.67 (95% CI 0.50–0.90) thereafter. The stratified log-rank test for OS reached statistical significance (P=0.03), although it did not meet the pre-specified threshold of P<0.0001.

Importantly, the addition of durvalumab did not increase grade 3–4 toxicity (71.6% vs 71.2%) or rates of delayed surgery (10.1% vs 10.8%, durvalumab vs placebo, respectively). Delayed initiation of adjuvant therapy occurred less frequently in the durvalumab group (2.3% vs 4.6%), suggesting the immunotherapy regimen is not only well-tolerated but may support more consistent treatment adherence.

Dr Janjigian concluded, “Despite receiving curative-intent surgery and chemotherapy, participants with gastric and gastroesophageal cancers frequently develop recurrent disease. Results from the MATTERHORN trial showed that more than two-thirds of participants treated with a durvalumab-based perioperative regimen were recurrence- and progression-free after 2 years. Though these results are promising, the pre-specified OS threshold was not reached, and the OS data is not yet mature, hampering interpretability.”

1. Janjigian Y, 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). Abstract LBA5, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.
2. Janjigian YY, et al. N Engl J Med 2025; Jun 1. DOI: 10.1056/NEJMoa2503701.

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Posted on 30 July 202530 July 2025