Fast track — ArticlesVandetanib 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
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.
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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
References (30)
- et al.
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial
Lancet
(2008) - et al.
Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument
Lung Cancer
(1995) - et al.
What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592
J Clin Epidemiol
(2002) - et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)
Lancet
(2005) - et al.
Quality of life in lung cancer: the validity and cross-cultural applicability of the Functional Assessment Of Cancer Therapy-Lung scale
Hematol Oncol Clin North Am
(2005) - et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Lancet
(2009) Cancer factsheet
- et al.
Cancer statistics, 2009
CA Cancer J Clin
(2009) - et al.
Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy
J Clin Oncol
(2000) - et al.
Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group
J Clin Oncol
(2000)
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy
J Clin Oncol
Erlotinib in previously treated non-small-cell lung cancer
N Engl J Med
Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis
Expert Opin Investig Drugs
ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration
Cancer Res
ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases
Cancer Res
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