title: Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.
abstract: BACKGROUND
  To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed.
  
  
  METHODS
  Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase.
  
  
  CONCLUSIONS
  Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.
  
  
  BACKGROUND
  
  
  
  BACKGROUND
  Clinicaltrials.gov
  
  
  BACKGROUND
  NCT00789373 TRIAL ABBREVIATION: H3E-EW-S124.
authors.affiliation: University Hospital - Virgen del Rocio, Seville, Spain. lpazares@hotmail.com
authors.forename: Luis G
authors.initials: LG
authors.lastname: Paz-Ares
authors.forename: Sedat
authors.initials: S
authors.lastname: Altug
authors.forename: Alexandra Thareau
authors.initials: AT
authors.lastname: Vaury
authors.forename: Jesús Corral
authors.initials: JC
authors.lastname: Jaime
authors.forename: Francesca
authors.initials: F
authors.lastname: Russo
authors.forename: Carla
authors.initials: C
authors.lastname: Visseren-Grul
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D004311:Double-Blind Method; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D010166:Palliative Care / Q000379:methods; D000068437:Pemetrexed; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012074:Remission Induction; D012107:Research Design; D055815:Young Adult
chemical_list: D005971:Glutamates; D010919:Placebos; D000068437:Pemetrexed; D006147:Guanine; D002945:Cisplatin