Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
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.



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.



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%]).



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.



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.
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kyoh@east.ncc.go.jp.
Kiyotaka
K
Yoh
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.
Takashi
T
Seto
Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
Miyako
M
Satouchi
Thoracic Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Makoto
M
Nishio
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Noboru
N
Yamamoto
Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
Haruyasu
H
Murakami
Department of Thoracic oncology, Shikoku Cancer Center, Matsuyama, Japan.
Naoyuki
N
Nogami
Division of Translational Research, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan.
Shingo
S
Matsumoto
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Takashi
T
Kohno
Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.
Koji
K
Tsuta
Division of Translational Research, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan.
Katsuya
K
Tsuchihara
Division of Pathology, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan.
Genichiro
G
Ishii
Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan.
Shogo
S
Nomura
Office of Clinical Trial Support, National Cancer Center Hospital East, Kashiwa, Japan.
Akihiro
A
Sato
Director, Exploratory Oncology Research and Clinical Trial Center, Center for Research and Administration and Support, National Cancer Center, Kashiwa, Japan.
Atsushi
A
Ohtsu
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Yuichiro
Y
Ohe
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Koichi
K
Goto
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D023061:Gene Order; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011799:Quinazolines / Q000008:administration & dosage*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C452423:vandetanib