Background: Poziotinib is an oral irreversible inhibitor of EGFR, HER2 and HER4, and has shown preclinical activity in lung cancer models with EGFR mutations including T790M. This phase II study was aimed to access the efficacy of poziotinib in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to erlotinib or gefitinib. Methods: Eligible patients had documented activating EGFRmutations and developed acquired resistance after treatment with erlotinib or gefitinib based on Jackman criteria. Patients received poziotinib at a dose of 16 mg once daily in 28-day cycles. The primary endpoint was PFS. All tumor responses were evaluated by independent review and, in a supportive manner, by investigator. Results: A total of 39 patients were treated with poziotinib in this study (29 women, median age 62 years [range, 43-84]). Most patients received erlotinib or gefitinib as first-line (n = 27) or second-line therapy (n = 11). The median time on erlotinib or gefitinib was 13.1 months (range, 3.4-33.2). Genotyping using tumor biopsy acquired at study entry was determined in 37 patients; 19 patients had EGFR T790M mutation, 2 PIK3CA mutation and no MET-amplification. Partial response with poziotinib was confirmed in 3 patients (8%; 95% CI, 2-21). Twenty patients (51%; 95% CI, 35-68) had disease control of at least stable disease for ≥ 8 weeks. The median PFS and overall survival were 2.7 (95% CI, 1.8-3.7) and 15.0 months (95% CI, 9.5-not estimable), respectively. The most frequently reported AEs of grade 3 by preferred term were rash (59%), stomatitis (18%), and diarrhoea (10%). Two patients were discontinued due to treatment-related AEs (one grade 3 rash and one grade 3 myositis). Conclusions: Poziotinib showed modest efficacy in patients with EGFR-mutant lung adenocarcinoma who had progressed on erlotinib or gefitinib. Obvious clinical evidence suggesting that poziotinib may overcome acquired resistance secondary to EGFR T790M mutation was not captured in this study. Clinical trial information: NCT01718847