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This Surveillance, Epidemiology, and End Results–Medicare analysis included 4033 patients receiving second-line therapy after first-line platinum-based therapy for newly diagnosed stage IIIB/IV non–small-cell lung cancer in the pre-immunotherapy era (2007 to mid-2013). Patients received a variety of second-line agents, most commonly pemetrexed, docetaxel, carboplatin/paclitaxel, and gemcitabine. Dyspnea and anemia were the most common AEs. Mean total per-patient–per-month cost was $10,885; and the prognosis was poor.Real-world data on current treatment practices for non–small-cell lung cancer (NSCLC) are needed to understand the place in therapy and potential economic impact of newer therapies.This retrospective cohort study identified patients ≥ 65 years old in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with first-time diagnosis of stage IIIB/IV NSCLC from 2007–2011 who received second-line therapy after first-line platinum-based chemotherapy from 2007 through mid-2013. Second-line regimens, health care resource use, adverse events (AEs), and associated costs were analyzed descriptively. Overall survival was determined by Kaplan-Meier test. Costs were adjusted to 2013 US dollars.We identified 4033 patients with advanced NSCLC who received second-line therapy (47% of those who received first-line platinum-based chemotherapy). Mean (SD) age was 73 (5) years, 2246 (56%) were male; 1134 (28%) and 2899 (72%) had squamous and nonsquamous NSCLC, respectively. The 4 most common second-line regimens were pemetrexed (22%), docetaxel (12%), carboplatin/paclitaxel (11%), and gemcitabine (7%). Median overall survival from second-line therapy initiation was 7.3 months (95% confidence interval, 7.0–7.7). Dyspnea and anemia were the most common AEs of interest, affecting 29% and 26% of patients, respectively; atypical pneumonia was associated with the highest AE-related costs (mean, $5339). The mean total per-patient–per-month cost was $10,885; AE-related per-patient–per-month costs totaled $1036 (10%). Costs were highest for pemetrexed-treated patients.These real-world data illustrate the variety of second-line regimens, poor prognosis, and high cost of second-line chemotherapy for patients with advanced NSCLC treated before the approval of immunotherapies for these patients.