9071 Background: Human epidermal growth factor 2 ( HER2, ERBB2) mutations have been identified as oncogenic drivers in 3% of lung cancers. Afatinib is an irreversible tyrosine kinase inhibitor of HER1 (EGFR), HER2 and HER4 and has been described in case reports to have activity in HER2-mutant lung cancers. However, there is little data to inform the clinical use of afatinib. Methods: We reviewed patients with metastatic HER2-mutant lung cancers treated with afatinib among 7 institutions between 2009 and 2016. The primary endpoint was investigator assessed overall response rate using RECIST v1.1. Other data collected included types of HER2mutations, duration of afatinib treatment and overall survival. Results: We identified 27 patients with metastatic HER2-mutant lung cancers treated with afatinib. Median age at diagnosis was 63 (range 40 to 84); majority were men (n = 16; 59%) and never-smokers (n = 18; 67%). All tumors were adenocarcinomas, and the majority were Stage IV at initial diagnosis (n = 16; 59%). A 12-base pair (bp) in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 16 patients (59%). In addition, there were three 9-bp insertions, two 3-bp insertions and two single bp substitutions (L755F and D769H) in exon 20; two single bp substitutions (S310F) in exon 8; one exon 17 V659E mutation; and one single-nucleotide polymorphism (Ile655Val). Median duration on afatinib was 2 months (range 1 to 27); median line of prior treatment was 3 (range 1 to 6). Eight patients had previously received trastuzumab prior to afatinib and one concurrently with afatinib. Overall response rate was 15% (n = 4; 95% CI 4 to 34%); the four partial responses lasted 5, 5, 6 and 10 months. The 3 longest partial responders had a 12-bp insertion in exon 20 (YVMA); the remaining partial responder had a 9-bp insertion in exon 20. Median overall survival from diagnosis date of metastatic disease was 23 months (95% CI 18 to 62). Conclusions: Afatinib produced partial responses in 15% of patients with metastatic HER2-mutant lung cancers, including insertion YVMA. Our findings confirm the activity of afatinib and provide data supporting a framework for its use in the care of patients with HER2-mutant lung cancers.