Background: Compared to chemotherapy, 1^st line treatment with EGFR-TK inhibitors results in superior progression-free survival (PFS) in Asian patients with advanced NSCLC with activating EGFR TK domain mutations. We conducted a prospective study with 1^st line erlotinib in Caucasian pts with EGFR TK domain mutations. Methods: Multicentre phase II study. EGFR mutation status was determined in a central lab on macro-dissected biopsies obtained from pts with advanced adenocarcinoma with a non- or past smoking history. Pts were given erlotinib, 150 mg daily till disease progression or prohibitive toxicity. The primary end point of the study was a 70% PFS at 3 months. Results: An EGFR mutation was found in 64 (28%) of 247 pts screened. Eighteen pts did not enter the study because of deterioration, withholding of consent after mutation analysis, or failing other clinical selection criteria. Forty six pts (8 male, 38 female) with median age of 72 years (35-83), median performance status of 1 (1-3) stage distribution Ib (1), IIIb (4) and IV (41) patients were included. EGFR mutations found: exon 18 (1), exon 19 (27), exon 20 (3) and exon 21 (15). Smoking history: 38 never smokers, 7 past smokers, 1 smoker. Median follow-up is 83 weeks. PFS was 83 % at 3 months and 74% at 6 months. Best response was: PR 26; SD 10, PD 10. The median time to progression and overall survival are not reached: 44+ and 56+ weeks respectively. One patient ended treatment prematurely because of skin toxicity while in PR for 83+ wks. Conclusions: In this the first formal prospective phase II genotype based study with erlotinib in first-line treatment of Caucasian pts with EGFR mutant advanced NSCLC, efficacy appears similar to the results obtained with gefitinib and erlotinib in randomized studies involving Asian patients and other first-line data with erlotinib. The study achieved its primary end point (PFS ≥ 70% at 3 months). A randomized study comparing first-line erlotinib versus chemotherapy is ongoing in Europe.