Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population.



This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate.



A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.



Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
S-H
SH
Lee
Department of Internal Medicine, Seoul National University Hospital, Seoul.
J-K
JK
Lee
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
M-J
MJ
Ahn
Department of Internal Medicine, Seoul National University Hospital, Seoul.
D-W
DW
Kim
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
J-M
JM
Sun
Department of Internal Medicine, Seoul National University Hospital, Seoul.
B
B
Keam
Department of Internal Medicine, Seoul National University Hospital, Seoul.
T M
TM
Kim
Department of Internal Medicine, Seoul National University Hospital, Seoul.
D S
DS
Heo
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
J S
JS
Ahn
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
Y-L
YL
Choi
Department of Pathology, Seoul National University Hospital, Seoul, Korea.
H-S
HS
Min
Department of Pathology, Seoul National University Hospital, Seoul, Korea.
Y K
YK
Jeon
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
K
K
Park
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010880:Piperidines / Q000627:therapeutic use*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011799:Quinazolines / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden
D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib
RET rearrangement; non-small cell lung cancer; vandetanib