title: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
abstract: BACKGROUND
  Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease.
  
  
  METHODS
  This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804.
  
  
  RESULTS
  All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001).
  
  
  CONCLUSIONS
  Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer.
  
  
  BACKGROUND
  Eli Lilly.
authors.affiliation: Oncological Institute Ion Chiricuta, Cluj, Romania.
authors.forename: Tudor
authors.initials: T
authors.lastname: Ciuleanu
authors.forename: Thomas
authors.initials: T
authors.lastname: Brodowicz
authors.forename: Christoph
authors.initials: C
authors.lastname: Zielinski
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzakowski
authors.forename: Eckart
authors.initials: E
authors.lastname: Laack
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Isabel
authors.initials: I
authors.lastname: Bover
authors.forename: Stephen
authors.initials: S
authors.lastname: Begbie
authors.forename: Valentina
authors.initials: V
authors.lastname: Tzekova
authors.forename: Branka
authors.initials: B
authors.lastname: Cucevic
authors.forename: Jose Rodrigues
authors.initials: JR
authors.lastname: Pereira
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Yang
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Madhavan
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Sugarman
authors.forename: Patrick
authors.initials: P
authors.lastname: Peterson
authors.forename: William J
authors.initials: WJ
authors.lastname: John
authors.forename: Kurt
authors.initials: K
authors.lastname: Krejcy
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005971:Glutamates / Q000009:adverse effects / Q000627:therapeutic use*; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine