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. 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.