Elsevier

The Lancet Oncology

Volume 11, Issue 7, July 2010, Pages 619-626
The Lancet Oncology

Fast track — Articles
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

https://doi.org/10.1016/S1470-2045(10)70132-7Get rights and content

Summary

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/m2 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.

Funding

AstraZeneca.

Introduction

Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related death and most patients are diagnosed with NSCLC at an advanced stage of disease.1, 2 Many patients initially achieve clinical remission or disease stabilisation with first-line therapy, but nearly all experience disease progression and eventually die from advanced NSCLC. Several drugs are approved as second-line treatments for advanced NSCLC, including docetaxel,3, 4 pemetrexed,5 erlotinib,6 and gefitinib;7 however, none have been shown to be better in this setting. One strategy to improve efficacy and alleviate symptom burden, without increasing toxicity, is to combine chemotherapeutics with drugs that selectively target signalling pathways associated with lung-cancer progression.

Vandetanib (AstraZeneca, Macclesfield, UK) is a once-daily oral anticancer drug that targets vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signalling.8, 9 Vandetanib is also a potent inhibitor of rearranged during transfection (RET) tyrosine kinase, an important growth driver in some thyroid cancers10 and possibly other cancers.11 Simultaneous targeting of VEGFR and EGFR with vandetanib is supported by evidence from clinically relevant xenograft models of human NSCLC,12 which showed that vandetanib could abrogate primary and acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs). In some of these preclinical models, resistance to EGFR inhibitors was associated with increased expression of tumour-derived and host-derived VEGF. Both the VEGFR and EGFR signalling pathways are established therapeutic targets in patients with advanced NSCLC: bevacizumab, an anti-VEGF monoclonal antibody, prolonged survival when added to paclitaxel and carboplatin in previously untreated non-squamous advanced NSCLC13 (bevacizumab is not indicated in patients with squamous histology because of the risk of life-threatening haemoptysis), and the EGFR inhibitors gefitinib and erlotinib have shown single-agent activity in previously treated advanced NSCLC.6, 7

Phase 2 assessment of vandetanib has shown antitumour activity in advanced, previously treated NSCLC14, 15 and in hereditary medullary thyroid cancer.16 In patients with previously treated NSCLC, vandetanib 100 mg/day plus docetaxel improved progression-free survival (PFS; hazard ratio [HR] 0·64) and objective response rate (ORR) versus docetaxel alone.14 Additionally, exploratory subgroup analyses showed a greater PFS benefit in women (HR 0·31) than in men (HR 0·87) with vandetanib 100 mg plus docetaxel versus docetaxel alone. The trial also showed that vandetanib 100 mg plus docetaxel resulted in a longer PFS and was better tolerated than vandetanib 300 mg plus docetaxel.14 Overall, these phase 2 results provided the rationale for further assessment of vandetanib 100 mg/day plus docetaxel in the randomised, placebo-controlled, phase 3 study (Zactima in cOmbination with Docetaxel In non-smAll cell lung Cancer [ZODIAC]) reported here.

Section snippets

Study design and patients

ZODIAC was a multinational, randomised, double-blind, phase 3 study of vandetanib plus docetaxel (Sanofi-Aventis, Paris, France) versus placebo plus docetaxel in patients with locally advanced or metastatic NCSLC after progression following platinum-based first-line chemotherapy. The recent approval and increasing use of pemetrexed as first-line therapy in NSCLC suggest a continuing role for docetaxel as second-line therapy.

Eligibility criteria included age 18 years or older; histological or

Results

Between May, 2006, and April, 2008, 1391 patients recruited from 198 centres in 25 countries were randomly assigned to receive vandetanib plus docetaxel (n=694) or placebo plus docetaxel (n=697; figure 1). Patient characteristics and baseline demographics were similar in both treatment groups (table 1). At data cut-off (Aug 22, 2008), 1205 patients (87%) had progressed, 814 (59%) had died, and the median potential duration of follow-up was 12·8 months. The median number of docetaxel cycles in

Discussion

In this randomised, double-blind, international phase 3 study, vandetanib in combination with docetaxel significantly prolonged the time to disease progression, compared with placebo plus docetaxel, for patients with advanced metastatic NSCLC in the second-line setting. Patients in the vandetanib plus docetaxel group also had a higher ORR and longer time to deterioration in lung-cancer symptoms than did those in the placebo group.

The study was representative of the patient population receiving

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