Data from Blood mRNA Expression Profiling Predicts Survival in Patients Treated with Tremelimumab

Abstract

<div>Abstract<p><b>Purpose:</b> Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade.</p><p><b>Experimental Design:</b> Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (<i>P</i> < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab.</p><p><b>Results:</b> Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (<i>r</i> = 0.9939). A four-gene model, including cathepsin D (<i>CTSD</i>), phopholipase A2 group VII (<i>PLA2G7</i>), thioredoxin reductase 1 (<i>TXNRD1</i>), and interleukin 1 receptor–associated kinase 3 (<i>IRAK3</i>), predicted survival in the test population (<i>P</i> = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (<i>P</i> < 0.0001).</p><p><b>Conclusions:</b> Expression levels of <i>CTSD, PLA2G7, TXNRD1</i>, and <i>IRAK3</i> in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy. <i>Clin Cancer Res; 20(12); 3310–8. ©2014 AACR</i>.</p></div>