Johan F Vansteenkiste1, Byoung Chul Cho2, Tonu Vanakesa3, Tommaso De Pas4, Marcin Zielinski5, Moon Soo Kim6, Jacek Jassem7, Masahiro Yoshimura8, Jubrail Dahabreh9, Haruhiku Nakayama10, Libor Havel11, Haruhiko Kondo12, Tetsuya Mitsudomi13, Konstantinos Zarogoulidis14, Oleg A Gladkov15, Katalin Udud16, Hirohito Tada17, Hans Hoffman18, Anders Bugge19, Paul Taylor20, Emilio Esteban Gonzalez21, Mei Lin Liao22, Jianxing He23, Jean-Louis Pujol24, Jamila Louahed25, Muriel Debois25, Vincent Brichard25, Channa Debruyne25, Patrick Therasse25, Nasser Altorki26. 1. Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospital KU Leuven, Leuven, Belgium. Electronic address: johan.vansteenkiste@uzleuven.be. 2. Yonsei University College of Medicine, Seoul, South Korea. 3. North Estonian Regional Hospital, Oncology Department, Tallinn, Estonia. 4. Oncology Unit of Thymic Cancer, Rare Tumors and Sarcomas, Milan, Italy. 5. Department of Thoracic Surgery, Zakopane, Poland. 6. National Cancer Center, Goyang-si Kyunggi-do, South Korea. 7. Medical University of Gdansk, Gdansk, Poland. 8. Hyogo Cancer Center, Akashi City, Hyogo, Japan. 9. Athens Medical Centre, Marousi, Greece. 10. Kanagawa Cancer Center, Yokohama City, Japan. 11. Department of Pneumology and Thoracic Surgery, Prague, Czech Republic. 12. Shizuoka Cancer Center, Tokyo, Japan. 13. Aichi Cancer Center Hospital 1-1, Aichi, Japan. 14. Pulmonary Clinic, G Papanikolaou General Hospital of Thessaloniki, Aristotle University, Thessaloniki, Greece. 15. Regional Oncology Dispensary Medgorodok, Chelyabinsk, Russia. 16. Korányi National Institute of Pulmonology, Budapest, Hungary. 17. Osaka City General Hospital, Osaka, Japan. 18. Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany. 19. Oslo University Hospital, Rikshospitalet, Oslo, Norway. 20. University Hospital of South Manchester, Manchester, UK. 21. Hospital Central de Asturias, Oviedo, Spain. 22. Shanghai Chest Hospital, Shanghai, China. 23. The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China. 24. Arnaud de Villeneuve Hospital, Montpellier, France. 25. GSK Vaccines, Rixensart, Belgium. 26. Joan and Sanford I Weill Medical College of Cornell University, New York, NY, USA.
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-positiveNSCLC 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 receivedchemotherapy, 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.
RCT Entities:
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.
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: Sachet A Shukla; Pavan Bachireddy; Bastian Schilling; Christina Galonska; Qian Zhan; Clyde Bango; Rupert Langer; Patrick C Lee; Daniel Gusenleitner; Derin B Keskin; Mehrtash Babadi; Arman Mohammad; Andreas Gnirke; Kendell Clement; Zachary J Cartun; Eliezer M Van Allen; Diana Miao; Ying Huang; Alexandra Snyder; Taha Merghoub; Jedd D Wolchok; Levi A Garraway; Alexander Meissner; Jeffrey S Weber; Nir Hacohen; Donna Neuberg; Patrick R Potts; George F Murphy; Christine G Lian; Dirk Schadendorf; F Stephen Hodi; Catherine J Wu Journal: Cell Date: 2018-04-12 Impact factor: 41.582