7575 Background: Phase II study showed first-line erlotinib (Erl) produced promising efficacy in advance NSCLC pts with EGFR Muts. This phase III trial compared PFS and safety of first-line Erl versus chemotherapy (chemo) in EGFR Mut pts with advanced NSCLC. Methods: Chemonaive NSCLC pts (stage IIIB or IV) with ECOG PS of 0-2, measurable disease and EGFR exon 19 or L858R Muts were eligible. Direct sequencing was used to detect EGFR Muts. The pts were randomized to receive Erl 150 mg/d up to PD or intolerable toxicities or to receive GEM (1,000 mg/m2 d1+d8) plus CBDCA (AUC=5, d1) up to 4 cycles. First endpoint was PFS and second endpoints included OS, safety, and QoL. Results: 549 pts were screened, 186 were found to have EGFR Muts (34.3%) and 165 pts were randomized. Safety was evaluable in 155 pts. One pt in Erl arm was not eligible but received 1 cycle of Erl. 10 pts in chemo arm withdrew informed consent and did not receive chemo. Demographic characteristics were comparable (Erl vs chemo), age 56.5 vs 58.8; M/F 41.5%/58.5% vs 40.3%/59.7%, adenocarcinoma /nonadenocarcinoma 87.8%/12.2% vs. 86.1%/13.9%, non-/ex-/current smokers 72%/7.3%/20.7% vs. 66.7%/8.3%/25%, EGFR exons 19/21 Muts 53.7%/46.3% vs. 54.2%/45.8%. Median follow-up time was 4.1 months and PFS in Erl arm is not mature yet. Dose reduction was reported in 4 cases in Erl arm (4.9%) and 18 cases in chemo arm (25.0%) (p<0.001) and dose reduction or interruption of GEM on day 8 was seen in 41.7% of pts. The Table lists the most common adverse events. There was no toxic death or ILD. Conclusions: First-line erlotinib is better tolerated and no new safety signals are found. Efficacy of the study is being followed up and will be reported at the Meeting. Adverse events Adverse events Erlotinib (N = 83) (%) Chemotherapy (N = 72) (%) All AE 75.9 Grades 3-4 8.4 All AE 88.9 Grades 3-4 56.9 Drug-related AE 63.9 NA 86.1 NA SAE 6.0 NA 6.9 NA Anemia 2.4 0 55.6 5.6 Neutropenia 3.6 0 56.9 37.5 Thrombocytopenia 1.2 0 56.9 36.1 Alanine aminotransferase increased 8.4 1.2 11.1 1.4 Skin rash 59 1.2 19.4 0 Vomiting 1.2 0 33.3 0 Diarrhea 20.5 1.2 2.8 0 Retinal detachment 1.2 1.2 0 0 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche