OBJECTIVES: Often new treatment options lack comparisons to treatment options which already exist on the market and which were launched several years ago. Due to such a lack of head-to-head evidence indirect treatment comparisons (ITC) are increasingly being performed. Although ITC methods are widely accepted, the results are often interpreted with caution, probably because of their lack of external validity proven by real clinical studies. METHODS: The first available pivotal phase-III trials for docetaxel and erlotinib in second-line non-small cell lung cancer (NSCLC) included best supportive care (BSC) as a comparator which allowed an ITC of erlotinib versus docetaxel to be performed, applying the Bucher methodology. The pemetrexed pivotal phase-III trial provided direct evidence vs docetaxel, which subsequently allowed an ITC of erlotinib vs pemetrexed to be performed. Later another phase-III trial was published comparing erlotinib vs pemetrexed, which allowed the ITC of erlotinib vs docetaxel to be re-performed. This trial and a further recently published phase-III trial directly comparing erlotinib vs docetaxel or pemetrexed, allowed the external validation of the ITC outcomes. The overall survival (OS) hazard ratios (HR) were used to produce ITC-OS HRs with 95% confidence intervals (95%CI). RESULTS: Comparing erlotinib versus docetaxel resulted in an ITC-OS HR of 1.25 (95%CI: 0.76-2.06, p=0.381). Using these ITC results to compare erlotinib to pemetrexed resulted in an ITC-OS HR of 1.26 (95%CI: 0.74-2.15, p=0.392). Re-performing the ITC of erlotinib versus docetaxel resulted in an ITC-OS HR of 0.95 (95%CI: 0.71-1.28, p=0.736). The head-to-head evidence validated those findings with an OS HR of 0.96 (95%CI: 0.77-1.21, p=0.916) and 0.96 (95%CI: 0.78-1.19, p=0.730), comparing erlotinib vs pemetrexed and erlotinib versus pemetrexed or docetaxel, respectively. CONCLUSIONS: Recently published clinical head-to-head evidence has confirmed the appropriateness and validity of ITC findings in second-line NSCLC.