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

Eur J Cancer. 2013 Oct;49(15):3111-21. doi: 10.1016/j.ejca.2013.06.035. Epub 2013 Jul 24.


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.

Findings: 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.

Interpretation: Pemetrexed-erlotinib significantly improved PFS compared to either drug alone in this clinically selected population. The combination had more toxicity, but was clinically manageable.

Trial registration: NCT00550173.

Keywords: Erlotinib; Never smoker; Non-small cell lung cancer; Pemetrexed; Phase 2.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Disease Progression
  • Disease-Free Survival
  • Erlotinib Hydrochloride
  • Female
  • Glutamates / administration & dosage
  • Glutamates / adverse effects
  • Glutamates / therapeutic use*
  • Guanine / administration & dosage
  • Guanine / adverse effects
  • Guanine / analogs & derivatives*
  • Guanine / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Pemetrexed
  • Proportional Hazards Models
  • Quinazolines / administration & dosage
  • Quinazolines / adverse effects
  • Quinazolines / therapeutic use*


  • Glutamates
  • Quinazolines
  • Pemetrexed
  • Guanine
  • Erlotinib Hydrochloride

Associated data