Kiyotaka Yoh1, Takashi Seto2, Miyako Satouchi3, Makoto Nishio4, Noboru Yamamoto5, Haruyasu Murakami6, Naoyuki Nogami7, Shingo Matsumoto8, Takashi Kohno9, Koji Tsuta10, Katsuya Tsuchihara8, Genichiro Ishii11, Shogo Nomura12, Akihiro Sato13, Atsushi Ohtsu14, Yuichiro Ohe5, Koichi Goto15. 1. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kyoh@east.ncc.go.jp. 2. Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan. 3. Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan. 4. Thoracic Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 5. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. 6. Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan. 7. Department of Thoracic oncology, Shikoku Cancer Center, Matsuyama, Japan. 8. Division of Translational Research, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan. 9. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. 10. Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan. 11. Division of Pathology, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan. 12. Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan. 13. Office of Clinical Trial Support, National Cancer Center Hospital East, Kashiwa, Japan. 14. Director, Exploratory Oncology Research and Clinical Trial Center, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan. 15. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Abstract
BACKGROUND: RET 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. METHODS: In 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. FINDINGS: Between 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%]). INTERPRETATION: Vandetanib 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. FUNDING: The 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.
BACKGROUND: RET 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. METHODS: In 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. FINDINGS: Between 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%]). INTERPRETATION: Vandetanib 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. FUNDING: The 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.
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