BACKGROUND: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

Azienda Ospedaliera Papa Giovanni XXIII Bergamo Italy

Charité Universitäetsmedizin Berlin Charité Campus Benjamin Franklin Berlin Germany

Charité Universitäetsmedizin Berlin Charité Campus Virchow Klinikum Berlin Germany

CHRU de Lille Hôpital Huriez Lille France

Department of Cancer Medicine Institut Gustave Roussy Villejuif France

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Haematology and Oncology Klinikum rechts der Isar Technische Universitaet Muenchen Munich Germany

Department of Medical Oncology ICO Badalona Barcelona Spain

Department of Medicine Leipzig Germany

Department of Oncology Rambam Health Care Campus Haifa Israel

Department of Oncology SLK Kliniken Heilbronn Heilbronn Germany

Department of Pathology Amsterdam UMC location VUmc Cancer Center Amsterdam VU University Amsterdam The Netherlands

Division of Surgery and Oncology Department of Clinical Science Intervention and Technology Karolinska Institutet Solna Sweden; Department of Upper Abdominal Diseases Karolinska University Hospital Stockholm Sweden

European Organisation for Research and Treatment of Cancer Headquarters Brussels Belgium

Hôpital Privé Jean Mermoz Lyon France

Hospital Clinico Universitario De Valencia Incliva Biomedical Research Institute Valencia Spain

Hospital Universitario 12 De Octubre Madrid Spain

Hospital Universitario de Navarra Instituto de Investigación Sanitaria de Navarra Pamplona Spain

Istituto Europeo di Oncologia IRCCS Milan Italy

Istituto Nazionale Tumori IRCCS Fondazione G Pascale Naples Italy

Maria Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Oslo University Hospital Ullevaal Hospital Oslo Norway

Oxford NIHR Biomedical Research Centre Churchill Hospital Oxford UK

Rabin Medical Center Beilinson Hospital Petach Tikva Israel

Royal Marsden Hospital London UK

University College Hospital London UK

University Medical Center Hamburg Eppendorf Center of Oncology Hamburg Germany

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