Plenary: The MATTERHORN study

During the plenary session at ASCO 2025, Professor Yelena Janjigian (Memorial Sloan Kettering Cancer Center) presented the results from the MATTERHORN study. Prof Eric Van Cutsem and Prof Jeroen Dekervel, both working at the University Hospitals Leuven, discuss the results of this practice-changing study.

The MATTERHORN trial is a phase 3 study evaluating the addition of durvalumab, a PD-L1 inhibitor, to standard perioperative FLOT chemotherapy in patients with locally advanced, non-metastatic gastric cancer. Historically, treatment progressed from primary resection to perioperative chemotherapy with FLOT, which improved overall survival compared to earlier regimens like ECF. The MATTERHORN study aimed to build on this by incorporating immunotherapy. In the experimental arm, patients received four cycles of FLOT with two cycles of durvalumab before surgery, followed by another four cycles of FLOT and two more cycles of durvalumab postoperatively. After chemotherapy, patients continued durvalumab monotherapy for up to one year. The control arm received FLOT with placebo.

The primary endpoint was event-free survival, which includes disease progression, diagnosis of metastases at surgery, or death. The study met its primary endpoint, showing a statistically significant and clinically meaningful improvement in event-free survival with the addition of durvalumab. Pathologic complete response rates were also higher in the durvalumab arm, supporting enhanced tumour control. Although overall survival data are not yet mature, a trend favouring durvalumab was observed.

Importantly, the combination did not introduce unexpected safety concerns. Durvalumab and FLOT showed non-overlapping toxicity profiles, and no additional surgical complications were reported. Subgroup analyses suggested better efficacy in intestinal-type gastric cancer, but effects were seen across histologies. PD-L1 status, assessed using the TAP score rather than CPS, did not clearly predict benefit, and the treatment appeared effective even in PD-L1 negative patients. This raises questions about whether PD-L1 expression should influence treatment eligibility.

Overall, the MATTERHORN trial supports the use of durvalumab with FLOT as a new standard for fit patients with locally advanced gastric cancer, pending further data on overall survival and regulatory guidance. The results are considered a practice-changing advancement and were a key highlight at the ASCO meeting.