title: Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer.
abstract: BACKGROUND
  This randomised controlled phase 2 study compared pemetrexed and erlotinib in combination with either agent alone in terms of efficacy and safety as second-line treatment in a clinically selected population of never-smokers with non-squamous non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Patients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤2 were randomised to either: pemetrexed 500 mg/m(2) on day 1 plus erlotinib 150 mg daily on days 2-14; erlotinib 150 mg daily; or pemetrexed 500 mg/m(2) on day 1 of a 21-day cycle until discontinuation criteria were met. The primary endpoint, progression-free survival (PFS), was analysed using a multivariate Cox model. Firstly, a global comparison across the three arms was performed. If the global null hypothesis was rejected at a two-sided 0.2 significance level, pairwise comparisons of pemetrexed-erlotinib versus erlotinib or pemetrexed were then conducted using the same model. Statistical significance was claimed only if both global and pairwise null hypotheses were rejected at a two-sided 0.05 significance level.
  
  
  RESULTS
  A total of 240 patients (male, 35%; East Asian, 55%; ECOG PS 0-1, 93%) were included. A statistically significant difference in PFS was found across the three arms (global p=0.003), with pemetrexed-erlotinib significantly better than either single agent: HR=0.57, 95% confidence interval (CI): 0.40-0.81, p=0.002 versus erlotinib; HR=0.58, 95% CI: 0.39-0.85, p=0.005 versus pemetrexed. Median PFS (95% CI) was 7.4 (4.4, 12.9) months in pemetrexed-erlotinib, 3.8 (2.7, 6.3) months in erlotinib and 4.4 (3.0, 6.0) months in pemetrexed. Safety analyses showed a higher incidence of drug-related grade 3/4 toxicity in pemetrexed-erlotinib (60.0%) than in pemetrexed (28.9%) or erlotinib (12.0%); the majority being neutropenia, anaemia, rash and diarrhoea.
  
  
  CONCLUSIONS
  Pemetrexed-erlotinib significantly improved PFS compared to either drug alone in this clinically selected population. The combination had more toxicity, but was clinically manageable.
authors.affiliation: Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.forename: José
authors.initials: J
authors.lastname: Rodrigues-Pereira
authors.forename: Baohui
authors.initials: B
authors.lastname: Han
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Song
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Hoon-Kyo
authors.initials: HK
authors.lastname: Kim
authors.forename: Tarini Prasad
authors.initials: TP
authors.lastname: Sahoo
authors.forename: Raghunadharao
authors.initials: R
authors.lastname: Digumarti
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Sedat
authors.initials: S
authors.lastname: Altug
authors.forename: Mauro
authors.initials: M
authors.lastname: Orlando
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018450:Disease Progression; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D005971:Glutamates; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D000069347:Erlotinib Hydrochloride
keywords: Erlotinib; Never smoker; Non-small cell lung cancer; Pemetrexed; Phase 2