Durvalumab Plus FLOT Shows OS Improvement in Resectable Gastric Cancer

The addition of durvalumab (Imfinzi) to 5-fluorouracil, leucovorin (folinic acid), oxaliplatin, docetaxel (FLOT) demonstrated a statistically significant and clinically meaningful overall survival(OS) improvement in patients with resectable gastric/gastroesophageal junction (G/GEJ) adenocarcinoma compared with FLOT plus placebo, regardless of pathological status, according to findings from the phase 3 MATTERHORN trial (NCT04592913) presented at the 2025 European Society for Medical Oncology (ESMO) Congress.¹

With a data cutoff date of September 1, 2025, the final OS analysis of the intention-to-treat population yielded a hazard ratio (HR) of 0.78 (95% CI, 0.63–0.96; P =.021) comparing the investigational arm with the control arm, with a median OS not reached in either arm.

“The overall survival results of the MATTERHORN study strongly support the use of durvalumab plus chemotherapy with FLOT as a new global standard of care for patients with localized, [resectable, G/GEJ] adenocarcinoma,” said Josep Tabernero, MD, PhD, professor of Medicine, head of the Department of Medical Oncology at Vall d’Hebron University Hospital, and director of Vall d’Hebron Institute of Oncology, Barcelona, Spain, in the presentation.¹

Furthermore, a survival analysis stratified by demographic and clinical characteristics showed that OS improvement was consistent across most key subgroups. Notably, a similar improvement in OS was achieved regardless of PD-L1 status. In patients with PD-L1–positive disease (PD-L1 TAP ≥1%), the HR was 0.79 (95% CI, 0.63–0.99). The HR was 0.79 (95% CI, 0.41–1.50) in patients who were PD-L1-negative (PD-L1 TAP <1%), demonstrating identical HRs across groups.

Additional findings reported included an improvement in event-free survival (EFS), the study’s primary end point, among patients with any degree of pathological response and regardless of pathological nodal status at the time of the data cutoff on December 20, 2024.

What Are the Study Design and Patient Characteristics?

The phase 3 MATTERHORN trial was a global, randomized, double-blind, placebo-controlled study evaluating the efficacy of neoadjuvant-adjuvant durvalumab plus FLOT chemotherapy.² The study’s primary end point was EFS; key secondary end points included OS and pathological complete response (pCR).

The study population consisted of 948 patients with localized G/GEJ adenocarcinoma who were treatment-naive upon enrollment. Patients were enrolled from across Asia, Europe, North America, and South America; of note, according Tabernero, is that 20% of patients were from Asia. Patients were stratified by geographical region, clinical lymph node status, and PD-L1 expression.

For treatment, patients were randomly assigned 1:1 to receive either the durvalumab and FLOT combination or placebo plus FLOT (n = 474, both arms) in the neoadjuvant setting. Patients received 1500 mg of durvalumab or placebo plus FLOT for 2 cycles before undergoing surgical resection 4 to 8 weeks after their last dose.³ Following surgical resection recovery, patients received 1500 mg of durvalumab or placebo as adjuvant therapy for up to 1 year.

What Trial Data Have Been Previously Reported?

In 2023, interim results with a data cutoff on February 1, 2023 suggested a significant and clinically meaningful benefit in pCR and near-PCR, with response rates of 27% and 14% observed in the investigational and control arms, respectively.⁴ Earlier in 2025, results of a primary end point analysis published in The New England Journal of Medicine revealed a 2-year EFS rate of 67.4% in the investigational arm vs 58.5% in the control arm.⁵ A consistent and manageable safety profile between arms was depicted in both reports.^4,5

Disclosures: Tabernero declared a consulting role with Accent Therapeutics, Alentis Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Carina Biotech, Cartography Biosciences, Chugai Pharmaceutical, Daiichi Sankyo Company, Eli Lilly and Company, F. Hoffmann-La Roche AG, Genentech, Johnson & Johnson, Menarini Ricerche S.p.A, Merus N.V., MSD, Novartis, Ono Pharma USA, Peptomyc, Pfizer, Pierre Fabre, Quantro Therapeutics, Scandion Oncology, Scorpion Therapeutics, Servier, Sotio Biotech, Taiho Pharmaceutical, Takeda Pharmaceutical International AG, and Tolremo Therapeutics, and stocks with 1 TRIAL SP, Alentis Therapeutics, Oniria Therapeutics and Pangaea Oncology.

References

1. Tabernero, J. 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: ESMO 2025 Congress; October 17–20, 2025; Berlin, Germany. Abstract LBA81.
2. Assessing durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer. ClinicalTrials.gov. Updated April 3, 2025. Accessed October 17, 2025. https://tinyurl.com/5d6ek6vn
3. Janjigian YY, Van Cutsem E, Muro K, et al. MATTERHORN: phase III study of durvalumab plus FLOT chemotherapy in resectable gastric/gastroesophageal junction cancer. Future Oncol. 2022;18(20):2465-2473. doi:10.2217/fon-2022-0093
4. Janjigian YY, Al-Batran SE, Wainberg Za, et al. LBA73 Pathological complete response (pCR) to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Interim results of the global, phase III MATTERHORN study. Ann Oncol. 2023;34:S1315-S1316. doi: 10.1016/j.annonc.2023.10.074
5. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer. NEJM. 2025;393(3):217-230. doi: 10.1056/nejmoa2503701