Background: ARQ 197 (A) is a selective, oral, non–ATP-competitive, small-molecule inhibitor of the c-MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, proliferation, and metastasis. The EGFR tyrosine kinase inhibitor (TKI), erlotinib (E) is approved for the treatment of advanced or metastatic NSCLC after failure of ≥ 1 prior chemotherapy regimen. Resistance to EGFR TKI in EGFR mutation-positive NSCLC is associated with amplification of c-MET. A + EGFR TKI showed greater preclinical antitumor activity than either drug alone. A randomized, placebo-controlled, phase II study in previously-treated metastatic NSCLC patients (pts) showed that E + A prolongs progression free survival, overall survival (OS), and delays the onset of new metastases compared to E alone in pts with non-squamous NSCLC (J Clin Oncol 28:18s, 2010 (suppl; abstr LBA7502). Methods: A follow-up phase III trial has been initiated. Eligible patients must have locally advanced unresectable or metastatic non-squamous NSCLC previously treated with 1 or 2 lines of systemic anticancer therapy, of which one must be platinum-doublet therapy; pts must be EGFR TKI naïve; have ECOG performance status ≤ 1, adequate organ function; measurable disease by RECIST, and archival tumor tissue available for histology, EGFR, KRAS, and c-MET testing. Pts treated with only adjuvant therapy are eligible if progression occurred < 6 months after completion of treatment. Pts with clinically unstable CNS metastases are excluded. 988 pts are planned to be stratified by the number of prior therapies, gender, smoking history, EGFR and KRAS mutation status. Pts are randomized 1:1 to receive E+A or E + placebo until progression, unacceptable toxicity or other discontinuation criterion is met. This study is powered to detect a significant improvement in median OS in the E+A arm over E alone. Radiographic efficacy assessments will occur every 8 weeks. Pts discontinued from study treatment will be followed for survival. The study is sponsored by Daiichi Sankyo Inc. in collaboration with ArQule, Inc.