Journal Article

A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies

Gladwin, Amanda, Morten, John, Lee, Jin-Soo, Stevens, James, Vasselli, James, Gray, Neil, Ye, Qingqing, de Boer, Richard, Harrod, Grace, Ji, Qunsheng, Bigley, Graham, Zhang, Tianwei, Donald, Emma, Platt, Adam, Fu, Haihua, Dale, Angela, Herbst, Roy S, Elvin, Paul, Davies, Amanda, Su, Xinying, Blockley, Laura, Womack, Chris, Zheng, Li, Cresswell, Carl, Fan, Shuqiong, Read, Jessica, Williams, Victoria

2015

Overview

Background To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Methods Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. Results The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3–1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n  = 3; comparator, n  = 4). 2.8% ( n  = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% ( n  = 76) had low RET gene copy number gain (4–6 copies in ≥40% of tumor cells) and 8.3% ( n  = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET -rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. Conclusions We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. Trial registration Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).

• Publisher: BioMed Central,BioMed Central Ltd
• Subject: Aged / Analysis / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Care and treatment / Drug therapy / Female / Gene Amplification / Genetic aspects / Genetics / genomics and epigenetics / Health aspects / Health Promotion and Disease Prevention / Humans / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Male / Medicine/Public Health / Middle Aged / Oncology / Pharmaceutical industry / Piperidines - therapeutic use / Prevalence / Proto-Oncogene Proteins c-ret - genetics / Proto-Oncogene Proteins c-ret - metabolism / Quinazolines - therapeutic use / Research Article / Retrospective Studies / Surgical Oncology / Translocation, Genetic / Treatment Outcome / Tumors / Vascular endothelial growth factor