OBJECTIVES: Lung cancer is the most common cause of cancer-related deaths world-wide. Afatinib is a novel, potent, irreversible ErbB family blocker. In EGFR mutation-positive locally advanced and metastatic non-small cell lung cancer, afatinib shows superior effectiveness as a 1st-line treatment compared to standard-of-care chemotherapy. To date, no head-to-head trial results exist to compare the efficacy of afatinib to reversible EGFR TKIs, gefitinib or erlotinib. The analyses presented here attempt to fill this gap by means of a network meta-analysis (NMA). METHODS: A systematic literature review (2002-2012) identified the best available evidence. Results from afatinib’s pivotal trials (LUX-Lung 3, LUX-Lung 6) were added. A NMA following a Bayesian approach (in WinBUGS) was applied to estimate the relative treatment effects between afatinib, gefitinib and erlotinib. Outcomes of interest were progression free survival (PFS) and overall survival (OS). For PFS, results by investigator review were considered as not in all trials PFS was assessed independently. Versus erlotinib, afatinib’s results in the two most common EGFR mutations studied in erlotinib trials were considered. Sensitivity analyses were performed to confirm the robustness of results. RESULTS: 20 studies, including LUX-Lung 3 and LUX-Lung 6, were included; 19 reported OS, 14 reported PFS. Results from random effects models are reported. All comparisons versus reversible TKIs favoured afatinib, although in most analyses the upper credible interval limit exceeded 1. The estimated probability of afatinib being best regarding PFS in all mutations was 80% compared to 17% for erlotinib and 3% for gefitinib, and was 43% regarding OS compared to 13% for gefitinib and 3% for erlotinib. CONCLUSIONS: Afatinib consistently showed superior efficacy versus chemotherapy in the pivotal trials. In the absence of head-to-head trial results versus reversible TKIs, the NMA results suggest also potential superiority of afatinib for both PFS and OS when compared to erlotinib and gefitinib.