OBJECTIVES: Recent clinical trials have established superior efficacy of both erlotinib and pemetrexed as first-line maintenance therapies for metastatic non-small cell lung cancer (mNSCLC) over placebo. Results indicated that erlotinib improved survival for all histology types and pemetrexed improved survival in non-squamous patients. To date, there have been no head-to-head trials directly comparing the two agents. An indirect comparison analysis was performed to examine the relative efficacy of these two treatment regimens as maintenance treatment options following platinum-based first-line therapy. METHODS: An adjusted-matched indirect analysis approach was used to compare overall survival (OS) estimates in mNSCLC patients treated with erlotinib from SATURN versus pemetrexed patients from JMEN. Patient distributions of key characteristics between the two studies were unbalanced; JMEN trial patients had a better prognosis at baseline. Patient distributions observed in the pemetrexed study for race and smoking status were used to match erlotinib-treated patients using patient-level data from the SATURN trial, employing an adjusted matching approach to make the populations more comparable. A distribution of survival outcomes was derived from each of 1000 repeated random matching samples of the SATURN data, with 95% confidence intervals (CI) around the mean of the aggregate of all observed median OS survival estimates generated by ordering the outcome measures and identifying the 2.5-percentile observations.  To indirectly compare treatments, the median ratio (MR) for OS was calculated to approximate the hazard ratio. RESULTS: The estimated median OS after adjusted-matching  was 13.9 months (95% CI 10.9-16.8) for erlotinib, compared with the published median OS reported for pemetrexed of 13.4 months (95% CI: 11.9-15.9). Erlotinib patients had similar median OS compared to pemetrexed patients with an MR of 0.96 (0.95, 1.09). CONCLUSIONS: Erlotinib and pemetrexed are similarly efficacious in first-line maintenance NSCLC differing in other parameters than efficacy such as tolerability, administration and patient convenience.