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

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

Abstract

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).

Figures

Figure 1
Figure 1
Representative FISH images. (A) Unknown RET rearrangement, (B)RET-KIF5B fusion, (C)RET gene amplifications and (D) low RET gene copy number gain. (E) Loci for RET FISH probes.
Figure 2
Figure 2
Representative IHC images positive for RET expression. (A) Tumor biopsies and (B) resections. (C) Negative (weak) staining.

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