title: Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial.
abstract: OBJECTIVE
  Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer.
  
  
  METHODS
  Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m(2) every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments.
  
  
  RESULTS
  There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed.
  
  
  CONCLUSIONS
  This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.
authors.affiliation: Western Hospital, Melbourne, Australia.
authors.forename: Richard H
authors.initials: RH
authors.lastname: de Boer
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Arrieta
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Yang
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
authors.forename: Valorie
authors.initials: V
authors.lastname: Chan
authors.forename: Johann
authors.initials: J
authors.lastname: Raats
authors.forename: Filippo
authors.initials: F
authors.lastname: de Marinis
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Abratt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Blackhall
authors.forename: Peter
authors.initials: P
authors.lastname: Langmuir
authors.forename: Tsveta
authors.initials: T
authors.lastname: Milenkova
authors.forename: Jessica
authors.initials: J
authors.lastname: Read
authors.forename: Johan F
authors.initials: JF
authors.lastname: Vansteenkiste
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D001315:Australia; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008800:Mexico; D008875:Middle Aged; D000068437:Pemetrexed; D010880:Piperidines / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage; D018570:Risk Assessment; D012307:Risk Factors; D013019:South Africa; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D005971:Glutamates; D010880:Piperidines; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; C452423:vandetanib