OBJECTIVES: EGFR mutation-positive NSCLC represents a distinct subtype of NSCLC and its first-line treatment generally comprises erlotinib, gefitinib or afatinib. These agents have all shown progression-free survival improvement vs platinum-doublet chemotherapy (CT). However, a recent pair-wise meta-analysis of phase III clinical trials based on individual patient-level data (n=1231) demonstrated that the reversible EGFR TKIs, erlotinib and gefitinib, do not prolong overall survival (OS) vs CT, neither for the overall patient population nor for the individual mutation subtypes, exon 19 deletions (Del19) and L858R.Here, we present a broader pair-wise meta-analysis including studies of the irreversible ErbB family blocker afatinib vs CT, as well as studies of erlotinib and gefitinib. METHODS: Patients with common EGFR mutations (Del19 or L858R) treated with either afatinib (LUX-Lung 3, LUX-Lung 6), erlotinib (ENSURE, EURTAC, OPTIMAL) or gefitinib (IPASS, NEJ002, WJTOG3405) in phase III clinical trials vs CT were included. Pooled treatment estimates using the inverse variance weighted method were calculated for all TKI vs CT comparisons in patients with Del19 or L858R. RESULTS: In total, data from 1037 patients with Del19 and 816 patients with L858R mutations were analyzed. Afatinib significantly improved OS vs CT in patients with Del19 (HR [95% CI]: 0.59 [0.45‒0.77]). For patients with Del19 there was no significant difference in OS, compared with CT, for either erlotinib (HR [95% CI]: 1.03 [0.77‒1.38]) or gefitinib (HR [95% CI]: 0.90 [0.70‒1.17]). None of the agents improved OS vs CT in patients with L858R mutations (afatinib: HR [95% CI] 1.25 [0.91‒1.71]; erlotinib: 0.98 [0.72‒1.35]; gefitinib: 1.11 [0.81‒1.54]). CONCLUSIONS: No differences in OS were observed in the overall EGFR mutation-positive or the L858R population for afatinib, erlotinib, or gefitinib. In contrast to other TKIs, afatinib showed a significant OS benefit vs CT in Del19 patients. Lee C, et al. J Clin Oncol 2015;33(suppl):abstract 8072