Gene Expression Signature is A Potential Predictive Factor for Efficacy of Mage-A3 Antigen-Specific Cancer Immunotherapeutic (asci) As Adjuvant Therapy in Resected Stage Ib/Ii Non-Small Cell Lung Cancer (Nsclc)
Annals of oncology（2008）
Med Univ Gdansk
Abstract
7501 Background: A phase II randomized trial in 182 patients (pts) with completely resected stage IB or II MAGE-A3 (+) NSCLC comparing postoperative MAGE-A3 recombinant protein combined with an Adjuvant System to placebo (q3w x 5, followed by q3m x 8) showed a strong positive signal for activity (J Clin Oncol 25 Suppl 18:398S, 2007). We report here the analysis of gene expression profiling of tumors prior to treatment to identify a predictive signature that correlates with clinical activity of MAGE-A3 ASCI treatment. Methods: Microarray analysis (Affymetrix) was performed on 159 fresh-frozen tumor biopsies (MAGE-A3: 108; placebo: 51; stage IB: 109; stage II: 50). Clinical data on relapse are based on a median follow-up of 44 months. Results: Study of tumor samples from pts in the placebo arm led to identification of a gene signature associated with a high risk of postoperative relapse. The absence of this signature correlated with a very low relapse rate in stage IB pts: placebo 0%; MAGE-A3: 4%. In the MAGE-A3 treated pts with the high risk of relapse signature, we compared 10 biopsies from stage IB pts with recurrence to 10 pts without recurrence. A 25 regulated gene probe predicted benefit from MAGE-A3 treatment. The relevance of this signature was confirmed on the remaining 139 stage IB and II biopsies. The predictive signature improved clinical efficacy (disease-free interval) (HR in GP+: 0.57; HR in GP-: 0.78) with no impact on relapse rate in the placebo arm. The signature consisted of immune- related genes associated to the pre-therapeutic tumor microenvironment. Conclusions: We identified a gene expression signature associated with high risk of relapse. Pts with tumors not presenting this signature have a very low risk of relapse after surgery (<3%). We also described another signature that is predictive to clinical activity of the MAGE-A3 ASCI treatment. Selection of pts with this predictive signature increases clinical efficiency by a factor 2. Interestingly, this signature is also associated to clinical activity to MAGE-A3 in a study in metastatic melanoma. Data will be validated in the ongoing NSCLC adjuvant phase III study (MAGRIT). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline
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