BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

Cancer Research Center Moscow Russia

Centrum Medyczne Bieńkowski Klinika Chirurgii Plastycznej Bydgoszcz Poland; Department of Oncological Surgery Oncology Center Bydgoszcz Poland

Columbus Clinic Center Milan Italy

Département de Dermatologie Centre Hospitalier Universitaire Hôpital Saint Éloi Montpellier France

Department of Dermatology and Skin Cancers La Timone APHM Hospital Aix Marseille University Marseille France

Department of Dermatology Centre Hospitalier Universitaire Tours France; UFR de Médecine Université François Rabelais Tours France

Department of Dermatology Venereology and Allergology University Hospital Schleswig Holstein Kiel Germany

Department of Dermatooncology Hotel Dieu Nantes University Hospital Nantes France

Department of Medical Oncology Erasmus MC Cancer institute Rotterdam Netherlands

Department of Oncology and Medical Radiology Dnipropetrovsk State Medical Academy Dnipropetrovsk Ukraine

Department of Skin and Soft Tissue Tumours National Cancer Institute Kiev Ukraine

Department of Soft Tissue Bone Sarcoma and Melanoma Maria Sklodowska Curie Institute Oncology Center Warsaw Poland

Dermato oncology Department General University Hospital Prague Czech Republic

Dermatology Department Hôpital Robert Debré Université de Reims Champagne Ardenne Reims France

Division of Hematology and Oncology Department of Medicine University of Alabama at Birmingham Birmingham AL USA

GlaxoSmithKline Rixensart Belgium

GlaxoSmithKline Rixensart Belgium; Biostatistics Department Janssen Research and Development Beerse Belgium

GlaxoSmithKline Rixensart Belgium; Immunology Translational Medicine UCB Brussels Belgium

GlaxoSmithKline Rixensart Belgium; Laboratoires Servier Paris France

GlaxoSmithKline Rixensart Belgium; University Hospitals Leuven Leuven Belgium

GlaxoSmithKline Rixensart Belgium; ViaNova Biosciences Brussels Belgium

Instituto de Oncología Ángel H Roffo Universidad de Buenos Aires Buenos Aires Argentina

Medical Statistics Department of Biomedical Data Sciences Leiden University Medical Center Leiden Netherlands

Melanoma Immunology and Oncology Group Centenary Institute University of Sydney Sydney NSW Australia; Melanoma Institute Australia Sydney NSW Australia

Melanoma Institute Australia The University of Sydney Sydney NSW Australia

Melanoma Institute Australia The University of Sydney Sydney NSW Australia; Seattle Cancer Care Alliance University of Washington Seattle WA USA

Melanoma Sarcoma Unit Fondazione IRCCS Istituto Nazionale Tumori Milan Italy

Melanoma Unit Dermatology Department Hospital Clinic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras Instituto de Salud Carlos 3 Barcelona Spain

Petrov Research Institute of Oncology St Petersburg Russia

Queensland Melanoma Project Discipline of Surgery The University of Queensland Princess Alexandra Hospital Woolloongabba QLD Australia

Service d'Oncologie Médicale Hôpital François Mitterrand Pau France

Skin Cancer Center Hannover Department of Dermatology Hannover Medical School Hannover Germany

Swissmed Centrum Zdrowia Gdansk Poland; Department of Surgical Oncology Gdansk Medical University Gdansk Poland

UPMC Hillman Cancer Center Pittsburgh PA USA

Lancet Oncol. 2018 Jul;19(7):852-853. doi: 10.1016/S1470-2045(18)30353-X. PubMed

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NCT00796445