title: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030-4009, USA. rherbst@mdanderson.org
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Wilfried E E
authors.initials: WE
authors.lastname: Eberhardt
authors.forename: Paul
authors.initials: P
authors.lastname: Germonpré
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Longyun
authors.initials: L
authors.lastname: Li
authors.forename: Fairooz
authors.initials: F
authors.lastname: Kabbinavar
authors.forename: Yukito
authors.initials: Y
authors.lastname: Ichinose
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Bonne
authors.initials: B
authors.lastname: Biesma
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Peter
authors.initials: P
authors.lastname: Langmuir
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Kennedy
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Tada
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D010880:Piperidines; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; C452423:vandetanib