• Kiyotaka Yoh, Takashi Seto, Miyako Satouchi, Makoto Nishio, Noboru Yamamoto, Haruyasu Murakami, Naoyuki Nogami, Shingo Matsumoto, Takashi Kohno, Koji Tsuta, Katsuya Tsuchihara, Genichiro Ishii, Shogo Nomura, Akihiro Sato, Atsushi Ohtsu, Yuichiro Ohe, and Koichi Goto.
• Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kyoh@east.ncc.go.jp.
• Lancet Respir Med. 2017 Jan 1; 5 (1): 42-50.

BackgroundRET rearrangements are rare oncogenic alterations in non-small-cell lung cancer (NSCLC). Vandetanib is a multitargeted tyrosine kinase inhibitor exhibiting RET kinase activity. We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC.MethodsIn this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. RET-positive patients were screened using a nationwide genomic screening network of about 200 participating institutions. Primary endpoint was the independently assessed objective response in eligible patients. This study is registered with UMIN-CTR, number UMIN000010095.FindingsBetween Feb 7, 2013, and March 19, 2015, 1536 patients with EGFR mutation-negative NSCLC were screened, of whom 34 were RET-positive (2%) and 19 were enrolled. Among 17 eligible patients included in primary analysis, nine (53% [95% CI 28-77]) achieved an objective response, which met the primary endpoint. In the intention-to-treat population of all 19 patients treated with vandetanib, nine (47% [95% CI 24-71]) achieved an objective response. At the data cutoff, median progression-free survival was 4·7 months (95% CI 2·8-8·5). The most common grade 3 or 4 adverse events were hypertension (11 [58%]), diarrhoea (two [11%]), rash (three [16%]), dry skin (one [5%]), and QT prolongation (two [11%]).InterpretationVandetanib showed clinical antitumour activity and a manageable safety profile in patients with advanced RET-rearranged NSCLC. Our results define RET rearrangement as a new molecular subgroup of NSCLC suitable for targeted therapy.FundingThe Ministry of Health, Labour and Welfare of Japan and the Practical Research for Innovation Cancer Control from the Japan Agency for Medical Research and Development, AMED.Copyright © 2017 Elsevier Ltd. All rights reserved.

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