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Clinical Trial
. 2010 Jul;11(7):619-26.
doi: 10.1016/S1470-2045(10)70132-7.

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

Roy S Herbst  1 , Yan Sun, Wilfried E E Eberhardt, Paul Germonpré, Nagahiro Saijo, Caicun Zhou, Jie Wang, Longyun Li, Fairooz Kabbinavar, Yukito Ichinose, Shukui Qin, Li Zhang, Bonne Biesma, John V Heymach, Peter Langmuir, Sarah J Kennedy, Hiroomi Tada, Bruce E Johnson
Affiliations
Clinical Trial

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

Roy S Herbst et al. Lancet Oncol. 2010 Jul.

Abstract

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.

Findings: 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).

Interpretation: The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy.

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Conflict of interest statement

Conflicts of interest

RSH received fees for consultancy (AstraZeneca steering committee) and grant support from AstraZeneca. WEEE received fees for an advisory board (ZODIAC steering committee) and a speaker’s bureau from AstraZeneca. PG received fees for an advisory board (ZODIAC steering committee) and accommodation expenses from AstraZeneca. YI received fees for honoraria from AstraZeneca. LZ received fees from AstraZeneca for presentation of data from this study at a regional meeting. JVH received fees for consultancy, grants, and honoraria from AstraZeneca. PL, SJK, and HT are employees of AstraZeneca and PL has stock in the company. BEJ received grant support, consultancy and honoraria fees (ZODIAC steering committee), and travel support from AstraZeneca. All other authors declared no conflicts of interest.

Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) in the intention-to-treat population (all randomised patients)
Figure 3
Figure 3. Hazard ratios for progression-free survival (A) and overall survival (B) by patient and clinical characteristics in the intention-to-treat population (all randomised patients)
Analyses were done using a log-rank test with treatment as the only factor.
Figure 4
Figure 4. Kaplan-Meier estimates of time to deterioration in symptoms (FACT-L, Lung Cancer Subscale) in the intention-to-treat population (all randomised patients)
FACT-L=Functional Assessment of Cancer Therapy-Lung questionnaire
See this image and copyright information in PMC

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