PurposeThis randomized, open-label trial evaluated erlotinib, an inhibitor of human epidermal growth factor receptor (EGFR), and a combination of erlotinib with fulvestrant, an anti-estrogen, in patients with advanced non-small cell lung cancer (NSCLC).Patients and MethodsPatients with NSCLC were randomly assigned at a ratio of 2:1 to receive erlotinib plus fulvestrant or erlotinib. Eligibility requirements included ECOG performance status 0-2, no prior EGFR-directed therapy, and previous treatment with one or more chemotherapy regimens unless patient refused. Primary end point was objective tumor response rate; additional endpoints included overall survival (OS), progression free survival (PFS) and safety.Results106 patients were randomized and 100 patients (evaluated population) received at least one dose of study drug. The overall response rate (RR) for the cohort was 20.7%: 14.3% in erlotinib arm and 24.3% in erlotinib plus fulvestrant arm. Median PFS was 1.8 months for erlotinib and 1.9 for erlotinib plus fulvestrant (HR=.85, 95% CI, .55-1.33, and p=0.47). Median OS was 5.7 months for erlotinib versus 9.4 months for erlotinib plus fulvestrant (HR=0.96, 95% CI, 0.6 to 1.55, and p=0.88). Response rate was significantly correlated with EGFR mutational status (p<0.0001). For patients with wild-type EGFR, clinical benefit rate (CBR: partial response + stable disease) was 54.8% with erlotinib plus fulvestrant versus 8.3% with erlotinib (p=0.0056). Common treatment-related adverse events were dermatological and gastrointestinal, predominantly grade 1 to 2.ConclusionWe were not able to demonstrate superiority of erlotinib with fulvestrant with respect to objective tumor response, OS and PFS compared to erlotinib alone. As anticipated, EGFR mutations were strongly associated with favorable outcomes. Within the EGFR wild-type subset, CBR was superior in the combination arm, although this was a post-hoc analysis rather than a prospective secondary endpoint. Ongoing work is evaluating blood and tissue samples from study participants in an attempt to identify biomarkers with anti-estrogens.