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Journal of Thoracic Oncology:
doi: 10.1097/01.JTO.0000283143.53176.59
Profferred Paper Abstracts: Session B1: Novel Therapeutics I: Tuesday, September 4: Novel Therapeutics I, Tue, 13:45 - 15:30

Activity of MAGE-A3 cancer immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC): final results of a multi-center, double-blind, randomized, placebo-controlled phase II study: B1-05

Vansteenkiste, Johan1; Zielinksi, Marcin2; Linder, Albert3; Dahabre, Jubrail4; Esteban, Emilio5; Malinowski, Wojciech6; Jassem, Jacek7; Passlick, Bernward8; Lehmann, Frédéric9; Brichard, Vincent G.9

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1 Respiratory Oncology Unit (Pneumology) - Univ. Hosp. Leuven, Leuven, Belgium 2 Szpital Chorub Pluc, Zakopane, Poland 3 LungenKlinik, Hemer, Germany 4 Medical Centre, Athens, Greece 5 Hospital Central de Asturias, Oviedo, Spain 6 Szpital Kopernika, Tuszin, Poland 7 Klinika Onkologii Radiotherapii, Gdansk, Poland 8 University Klinik, Freiburg, Germany 9 GlaxoSmithKline Biologicals, Rixensart, Belgium

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Background:

NSCLC is associated with poor outcome: even after complete surgical resection, about half of the patients with stage IB or II NSCLC relapse and die within 5 years. Cisplatin-based adjuvant chemotherapy improves overall survival but at the expense of substantial toxicity. The MAGE-A3 gene is expressed specifically in tumor cells with no expression in normal cells. Pilot studies evaluating the MAGE-A3 cancer immunotherapeutic (i.e. MAGE-A3 recombinant protein combined with a potent GSK proprietary immunological adjuvant) showed a good tolerability and long-lasting clinical objective responses in metastatic melanoma. Because MAGE-A3 is significantly expressed in NSCLC (35% in stages IB or II), post-operative immunization with the MAGE-A3 cancer immunotherapeutic may be a tumor-specific, well tolerated, and effective adjuvant therapy.

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Methods:

Patients with completely resected, MAGE-A3 (+), pathological stage IB or II NSCLC were randomly assigned to postoperative intramuscular administrations of MAGE-A3 or placebo (2:1), with 5 administrations at 3-week intervals, followed by 8 administrations every 3 months. Stratification factors included stage (IB vs. II), histology (squamous carcinoma vs. other), and lymph-node procedure (minimal lymph-node sampling vs. radical mediastinal lymphadenectomy). The primary endpoint was disease-free interval; secondary endpoints were safety, disease-free survival, and overall survival. This Phase II study (study ID249553/004/NCT00290355) was designed to detect a clinically relevant hazard ratio with a 10% one-sided ?.

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Results:

1089 tumor samples were examined, of which 363 expressed the MAGE-A3 gene. 182 patients (122 stage IB, 60 stage II) from 59 centers in 14 European countries were randomized over 2 years. The patient characteristics are the following: Median age 63 (45-81); 87% male; 65% squamous cell carcinoma; 65% systematic radical mediastinal lymphadenectomy. After a median follow-up of 28 months, 67 recurrences were observed. Group comparisons of disease-free interval, disease-free survival, and overall survival gave respectively a hazard ratio of 0.74 (95% CI 0.44-1.20, p=0.107), 0.73 (95% CI 0.45-1.16, p = 0.093) and 0.66 (95% CI 0.36-1.20, p = 0.088) in favor of the MAGE-A3 group. Overall, treatment was well tolerated. Subset analysis suggests that systematic radical mediastinal lymphadenectomy may have a positive effect on survival.

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Conclusions:

The final analysis of this randomized Phase II study shows a positive signal for clinical activity of MAGE-A3 cancer immunotherapeutic as adjuvant treatment in completely resected Stage IB or II NSCLC. The relative improvement in disease-free interval and disease-free survival is 27%. This treatment is well tolerated. Further Phase III evaluation in early NSCLC is planned for 2007.

Copyright © 2007 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.

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