Brigitte Dreno1, John F Thompson2, Bernard Mark Smithers3, Mario Santinami4, Thomas Jouary5, Ralf Gutzmer6, Evgeny Levchenko7, Piotr Rutkowski8, Jean-Jacques Grob9, Sergii Korovin10, Kamil Drucis11, Florent Grange12, Laurent Machet13, Peter Hersey14, Ivana Krajsova15, Alessandro Testori16, Robert Conry17, Bernard Guillot18, Wim H J Kruit19, Lev Demidov20, John A Thompson21, Igor Bondarenko22, Jaroslaw Jaroszek23, Susana Puig24, Gabriela Cinat25, Axel Hauschild26, Jelle J Goeman27, Hans C van Houwelingen27, Fernando Ulloa-Montoya28, Andrea Callegaro29, Benjamin Dizier30, Bart Spiessens31, Muriel Debois29, Vincent G Brichard32, Jamila Louahed29, Patrick Therasse33, Channa Debruyne34, John M Kirkwood35. 1. Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. 2. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. 3. Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. 4. Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 5. Service d'Oncologie Médicale, Hôpital François Mitterrand, Pau, France. 6. Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. 7. Petrov Research Institute of Oncology, St Petersburg, Russia. 8. Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. 9. Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. 10. Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine. 11. Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland. 12. Dermatology Department, Hôpital Robert Debré, Université de Reims Champagne-Ardenne, Reims, France. 13. Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Médecine, Université François-Rabelais, Tours, France. 14. Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. 15. Dermato-oncology Department, General University Hospital, Prague, Czech Republic. 16. Columbus Clinic Center, Milan, Italy. 17. Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. 18. Département de Dermatologie, Centre Hospitalier Universitaire, Hôpital Saint-Éloi, Montpellier, France. 19. Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands. 20. Cancer Research Center, Moscow, Russia. 21. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. 22. Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. 23. Centrum Medyczne Bieńkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland. 24. 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. 25. Instituto de Oncología Ángel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina. 26. Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany. 27. Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. 28. GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com. 29. GlaxoSmithKline, Rixensart, Belgium. 30. GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium. 31. GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium. 32. GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium. 33. GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France. 34. GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium. 35. UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Abstract
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 forplacebo). 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.
RCT Entities:
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.
Authors: Marit M Melssen; Karlyn E Pollack; Max O Meneveau; Mark E Smolkin; Joel Pinczewski; Alexander F Koeppel; Stephen D Turner; Katia Sol-Church; Alexandra Hickman; Donna H Deacon; Gina R Petroni; Craig L Slingluff Journal: Cancer Immunol Immunother Date: 2021-01-16 Impact factor: 6.968
Authors: Diane M Da Silva; Joseph G Skeate; Elena Chavez-Juan; Kim P Lühen; Jiun-Ming Wu; Chia-Mao Wu; W Martin Kast; KinKai Hwang Journal: Vaccine Date: 2019-04-19 Impact factor: 3.641
Authors: Rebecca R Florke Gee; Helen Chen; Anna K Lee; Christina A Daly; Benjamin A Wilander; Klementina Fon Tacer; Patrick Ryan Potts Journal: J Biol Chem Date: 2020-09-13 Impact factor: 5.157