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).
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.
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).
The addition of vandetanib to docetaxel provides a significant improvement in PFS
in patients with advanced NSCLC after progression following first-line therapy.
2010 Elsevier Ltd. All rights reserved.