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.

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.

• Authors: Roy S Herbst, 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
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 11 Issue 7 Pg. 619-26 (Jul 2010) ISSN: 1474-5488 [Electronic] England
• PMID: 20570559 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Piperidines
• Quinazolines
• Taxoids
• Docetaxel
• vandetanib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Asian People
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Disease-Free Survival
• Docetaxel
• Double-Blind Method
• Female
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Piperidines (administration & dosage, adverse effects)
• Proportional Hazards Models
• Quinazolines (administration & dosage, adverse effects)
• Survival Analysis
• Taxoids (administration & dosage, adverse effects)