title: Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC.
  
  
  METHODS
  In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025.
  
  
  RESULTS
  Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]).
  
  
  CONCLUSIONS
  Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped.
  
  
  BACKGROUND
  GlaxoSmithKline Biologicals SA.
authors.affiliation: Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospital KU Leuven, Leuven, Belgium. Electronic address: johan.vansteenkiste@uzleuven.be.
authors.forename: Johan F
authors.initials: JF
authors.lastname: Vansteenkiste
authors.affiliation: Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
authors.affiliation: North Estonian Regional Hospital, Oncology Department, Tallinn, Estonia.
authors.forename: Tonu
authors.initials: T
authors.lastname: Vanakesa
authors.affiliation: Oncology Unit of Thymic Cancer, Rare Tumors and Sarcomas, Milan, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Pas
authors.affiliation: Department of Thoracic Surgery, Zakopane, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Zielinski
authors.affiliation: National Cancer Center, Goyang-si Kyunggi-do, South Korea.
authors.forename: Moon Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Medical University of Gdansk, Gdansk, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.affiliation: Hyogo Cancer Center, Akashi City, Hyogo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yoshimura
authors.affiliation: Athens Medical Centre, Marousi, Greece.
authors.forename: Jubrail
authors.initials: J
authors.lastname: Dahabreh
authors.affiliation: Kanagawa Cancer Center, Yokohama City, Japan.
authors.forename: Haruhiku
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Pneumology and Thoracic Surgery, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Havel
authors.affiliation: Shizuoka Cancer Center, Tokyo, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Aichi Cancer Center Hospital 1-1, Aichi, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Pulmonary Clinic, G Papanikolaou General Hospital of Thessaloniki, Aristotle University, Thessaloniki, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Zarogoulidis
authors.affiliation: Regional Oncology Dispensary Medgorodok, Chelyabinsk, Russia.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Gladkov
authors.affiliation: Korányi National Institute of Pulmonology, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Udud
authors.affiliation: Osaka City General Hospital, Osaka, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tada
authors.affiliation: Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Hoffman
authors.affiliation: Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Bugge
authors.affiliation: University Hospital of South Manchester, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Emilio Esteban
authors.initials: EE
authors.lastname: Gonzalez
authors.affiliation: Shanghai Chest Hospital, Shanghai, China.
authors.forename: Mei Lin
authors.initials: ML
authors.lastname: Liao
authors.affiliation: The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China.
authors.forename: Jianxing
authors.initials: J
authors.lastname: He
authors.affiliation: Arnaud de Villeneuve Hospital, Montpellier, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pujol
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Jamila
authors.initials: J
authors.lastname: Louahed
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Debois
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Brichard
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Channa
authors.initials: C
authors.lastname: Debruyne
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Therasse
authors.affiliation: Joan and Sanford I Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Nasser
authors.initials: N
authors.lastname: Altorki
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D018796:Immunoconjugates; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins