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

Abstract

BackgroundTo 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.MethodsArchival 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.ResultsThe 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.ConclusionsWe 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 registrationRandomized Phase III clinical trials (NCT00312377, ZODIAC; NCT00418886, ZEAL; NCT00364351, ZEST; NCT00404924, ZEPHYR).Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1146-8) contains supplementary material, which is available to authorized users.

Expression and copy number gains of the RET gene in 631 early and mid stage non‐small cell lung cancer cases

“…A retrospective analysis conducted by Platt et al . yielded an RET expression rate of 11.6% (40/346) in Asians, which is much higher than our result. Differences in tumor staging may have caused our lower RET expression rate.…”

RET protein is overexpressed in oral squamous cell carcinoma

“…Here, we demonstrate that RET is overexpressed in only a small subset of OSCCs. Overexpression of RET was also observed in previous studies on papillary thyroid cancer, NSCLC, breast cancer, pancreatic cancer, and prostate cancer . RET overexpression rates varied among these types of cancer and OSCC, although different scoring methods and thresholds were used.…”

“…Interestingly, Platt et al . did not identify RET rearrangements, RET copy‐number changes or the level of RET expression as predictive markers for the response to vandetanib in NSCLC patients …”

“…Overexpression of RET was also observed in previous studies on papillary thyroid cancer, NSCLC, breast cancer, pancreatic cancer, and prostate cancer. 1,3,4 RET overexpression rates varied among these types of cancer and OSCC, although different scoring methods and thresholds were used. In this study, no RET rearrangements were detected in OSCCs.…”

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

“…Clinical responses to these drugs have been also reported for individual RET mutant patients with other malignancies. Partial responses were noted in RET fusion-positive ADC patients treated with cabozantinib or vandetanib (Drilon et al 2013; Gautschi et al 2013; Mukhopadhyay et al 2014; Platt et al 2015; Falchook et al 2016; Rosell et al. 2016; Lee et al 2016; Yoh et al 2017).…”