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. FINDINGS: 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%]). INTERPRETATION: 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. FUNDING: GlaxoSmithKline Biologicals SA.

Aichi Cancer Center Hospital 1 1 Aichi Japan

Arnaud de Villeneuve Hospital Montpellier France

Athens Medical Centre Marousi Greece

Department of Pneumology and Thoracic Surgery Prague Czech Republic

Department of Thoracic Surgery Zakopane Poland

GSK Vaccines Rixensart Belgium

Hospital Central de Asturias Oviedo Spain

Hyogo Cancer Center Akashi City Hyogo Japan

Joan and Sanford 1 Weill Medical College of Cornell University New York NY USA

Kanagawa Cancer Center Yokohama City Japan

Korányi National Institute of Pulmonology Budapest Hungary

Medical University of Gdansk Gdansk Poland

National Cancer Center Goyang si Kyunggi do South Korea

North Estonian Regional Hospital Oncology Department Tallinn Estonia

Oncology Unit of Thymic Cancer Rare Tumors and Sarcomas Milan Italy

Osaka City General Hospital Osaka Japan

Oslo University Hospital Rikshospitalet Oslo Norway

Pulmonary Clinic G Papanikolaou General Hospital of Thessaloniki Aristotle University Thessaloniki Greece

Regional Oncology Dispensary Medgorodok Chelyabinsk Russia

Respiratory Oncology Unit Department of Respiratory Medicine University Hospital KU Leuven Leuven Belgium

Shanghai Chest Hospital Shanghai China

Shizuoka Cancer Center Tokyo Japan

The 1st Affiliated Hospital of Guangzhou Medical College Guangzhou China

Thoraxklinik Heidelberg gGmbH Heidelberg Germany

University Hospital of South Manchester Manchester UK

Yonsei University College of Medicine Seoul South Korea

Lancet Oncol. 2016 Jun;17(6):697-698. doi: 10.1016/S1470-2045(16)30031-6. PubMed

J Thorac Dis. 2016 Aug;8(8):1886-90. doi: 10.21037/jtd.2016.07.11. PubMed

J Thorac Dis. 2016 Oct;8(10):E1348-E1350. doi: 10.21037/jtd.2016.10.99. PubMed

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ClinicalTrials.gov
NCT00480025