Background: Dacomitinib, an irreversible pan-HER kinase inhibitor, has demonstrated anti-cancer activity in phase 2 studies for patients with EGFR activating mutation and in those with EGFR and K-RAS wild-type (WT) NSCLC. Methods: Patients (pts) with locally advanced/metastatic NSCLC were randomized following progression with 1 or 2 prior chemotherapy regimens to treatment with Dacomitinib (D) (45 mg PO QD) or Erlotinib (E) (150 mg PO QD) with placebo control for both arms. Archived tumor tissue, ECOG performance status (PS) of 0-2, adequate organ function and informed consent were required. The primary endpoint was progression-free survival (PFS) per independent review in the co-primary populations [all patients and those with KRAS WT]. The estimated sample size was 800 pts, using 1-sided stratified log rank test for all pts to detect HR≤ 0.75, at significance = 1.5% with 90% power and to detect HR≤ 0.69 for KRAS WT at significance = 1% with 80% power. Secondary endpoints: overall survival, objective response (OR), safety, and patient reported outcomes. Results: 878 pts with the following baseline characteristics were enrolled; approximate median age of 63 years, 64% males, 76% Caucasians, 90% with PS 0/1, 69% adenocarcinoma and 18% never-smokers. Activating EGFR mutation was present in 41 pts in each arm. Discontinuation for treatment-related toxicity was more frequent with D (8% vs. 4.8%). Diarrhea, stomatitis, paronychia, and mucositis were more common with D. Conclusions: Irreversible EGFR inhibition with Dacomitinib is not superior to Erlotinib in the second-/third-line therapy of advanced NSCLC. Overall survival and outcomes for pts with EGFR mutation are not mature. Clinical trial information: NCT01360554.