e19160 Background: Lung cancer is the leading cause of cancer-related deaths globally, with a 15% 5-year survival rate. Platinum-based chemotherapy constitutes the main treatment modality, with a median overall survival (OS) of approximately 10–12 months. The current National Comprehensive Cancer Network (NCCN) guidelines recommend several options for first-line and second-line therapies but endorse only erlotinib/gefitinib as third-line therapy in unselected patients, as well as crizotinib in ALK-positive selected patients.The paucity of approved agents for third-line therapy and beyond for patients with non-small cell lung cancer (NSCLC) constitutes an important unmet medical need. Methods: Retrospective analysis of 22 patients with advanced/metastatic NSCLC in progression after a minimum of 3 lines of therapy. Results: Between January 2009 and October 2012, 22 patients were analysed. Median age at diagnosis was 62 years old. 15% of patients were never smokers and 72.7% had non squamous NSCLC histology. Stage at diagnosis resulted: 6 (27.3%) stage IIIA, 3 (13.6%) stage IIIB and 13 (59.1%) stage IV. 3 (13.6%) patients were EGFR mutation carriers and 1(1%) patient had ALK translocation. Third line therapy options resulted a clinical trial (27.3%), erlotinib (22.7%), paclitaxel/gemcitabine (13.6%), docetaxel (9.1%) and crizotinib (4.5%). Estimated median progression-free survival (PFS) between first and second line therapy was 5.3 months; PFS between second and third line resulted 4.4 months. Median PFS and overall survival (OS) beyond third line treatment has not been reached yet. Conclusions: Currently, erlotinib/gefitinib and crizotinib, which target EGFR and ALK, are the only recommended agents for third-line therapy in patients with advanced/metastatic NSCLC. Real-world clinical practice reveals a variety of chemotherapeutic agents used in this setting. Additional systemic and/or targeted therapeutic under development, with complementary biomarker analysis, should be the key in identifying those patients most likely to benefit from newer agents.