Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial.
BACKGROUND
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC).


METHODS
Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m(2) intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377.


RESULTS
1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0.79, 97.58% CI 0.70-0.90; p<0.0001); median PFS was 4.0 months in the vandetanib group versus 3.2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0.79, 0.62-1.00, p=0.024); median PFS was 4.6 months in the vandetanib group versus 4.2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group).


CONCLUSIONS
The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy.
Herbst
Roy S
RS
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030-4009, USA. rherbst@mdanderson.org
Sun
Yan
Y
Eberhardt
Wilfried E E
WE
Germonpré
Paul
P
Saijo
Nagahiro
N
Zhou
Caicun
C
Wang
Jie
J
Li
Longyun
L
Kabbinavar
Fairooz
F
Ichinose
Yukito
Y
Qin
Shukui
S
Zhang
Li
L
Biesma
Bonne
B
Heymach
John V
JV
Langmuir
Peter
P
Kennedy
Sarah J
SJ
Tada
Hiroomi
H
Johnson
Bruce E
BE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects
D010880:Piperidines; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; C452423:vandetanib