LUX-Lung 3, an ongoing randomized, multicenter, open-label phase III trial, compares single-agent BIBW 2992 (afatinib) with standard pemetrexed/cisplatin chemotherapy as first-line treatment of stage IIIB/IV adenocarcinoma of the lung with epidermal growth factor receptor (EGFR)-activating mutations. BIBW 2992 is an investigational, orally administered irreversible EGFR-1 and human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor (TKI). The current trial (LUX-Lung 3) will randomize 330 patients in a 2:1 ratio to receive either BIBW 2992 or chemotherapy with pemetrexed/cisplatin. Patients will receive either BIBW 2992 at a starting dose of 40 mg once daily continuously or pemetrexed (500 mg/m² IV) and cisplatin (75 mg/m²) on day 1 of 21-day cycles. Patients will receive 6 cycles of chemotherapy unless unacceptable toxicity occurs. BIBW 2992 will be given continuously until disease progression occurs. The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response, disease control assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and overall survival. Oncologists may obtain information on how to enroll patients from the National Institutes of Health’s Web site (www.clinicaltrials.gov/ct2/show/NCT00949650).