MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

Autor:	Dreno B; Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France., Thompson JF; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia., Smithers BM; Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia., Santinami M; Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy., Jouary T; Service d'Oncologie Médicale, Hôpital François Mitterrand, Pau, France., Gutzmer R; Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany., Levchenko E; Petrov Research Institute of Oncology, St Petersburg, Russia., Rutkowski P; Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland., Grob JJ; Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France., Korovin S; Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine., Drucis K; Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland., Grange F; Dermatology Department, Hôpital Robert Debré, Université de Reims Champagne-Ardenne, Reims, France., Machet L; Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Médecine, Université François-Rabelais, Tours, France., Hersey P; Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia., Krajsova I; Dermato-oncology Department, General University Hospital, Prague, Czech Republic., Testori A; Columbus Clinic Center, Milan, Italy., Conry R; Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Guillot B; Département de Dermatologie, Centre Hospitalier Universitaire, Hôpital Saint-Éloi, Montpellier, France., Kruit WHJ; Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands., Demidov L; Cancer Research Center, Moscow, Russia., Thompson JA; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA., Bondarenko I; Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine., Jaroszek J; Centrum Medyczne Bieńkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland., Puig S; 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 III, Barcelona, Spain., Cinat G; Instituto de Oncología Ángel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina., Hauschild A; Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany., Goeman JJ; Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands., van Houwelingen HC; Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands., Ulloa-Montoya F; GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com., Callegaro A; GlaxoSmithKline, Rixensart, Belgium., Dizier B; GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium., Spiessens B; GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium., Debois M; GlaxoSmithKline, Rixensart, Belgium., Brichard VG; GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium., Louahed J; GlaxoSmithKline, Rixensart, Belgium., Therasse P; GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France., Debruyne C; GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium., Kirkwood JM; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2018 Jul; Vol. 19 (7), pp. 916-929. Date of Electronic Publication: 2018 Jun 13.
DOI:	10.1016/S1470-2045(18)30254-7
Abstrakt:	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. (Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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