OBJECTIVES: To estimate comparative efficacy of nivolumab±ipilimumab versus SOC for SCLC patients treated with two prior lines of chemotherapy/chemoradiotherapy using a population-adjusted indirect comparison. METHODS: A systematic literature review identified no randomized controlled trials evaluating 3L SCLC patients. Therefore, real-world data for this population were obtained from Flatiron Health electronic health record database from Jan-2011 to Sep-2017. The overall survival (OS) Kaplan Meier curve was constructed for a subgroup of SCLC patients who received a 3L treatment, at least one platinum-based regimen, and no immune-oncology agents (SOC n=78) with inclusion/exclusion criteria matched to patients in CheckMate 032. Individual patient data from CheckMate 032 for patients who received 3L nivolumab (n=78) or nivolumab+ipilimumab (n=43), respectively, were used to predict OS controlling for Eastern Cooperative Oncology Group performance status, platinum sensitivity, disease stage (i.e. extensive versus limited), and gender. These covariates were centered using the Flatiron target population. Constant and time-varying hazard ratios (HRs) were explored for the comparisons of interest using fractional polynomial models. RESULTS: SCLC chemotherapies (predominantly topotecan) evaluated in Flatiron for the 3L population delivered poor survival outcomes (median=3.8 months [95%CI: 2.8, 4.9]). OS HRs (95% credible intervals) from the naïve unadjusted indirect comparison were: nivolumab versus SOC 0.62 (0.42-0.90); and nivolumab+ipilimumab versus SOC 0.43 (0.27-0.69). Based on the population-adjusted indirect comparison, the HRs were: nivolumab versus SOC 0.68 (0.48-0.96); and nivolumab+ipilimumab versus SOC 0.50 (0.32-0.78). Time-varying hazard ratios were not justified based on the deviance information criteria. Estimates from sensitivity analyses using matched-adjusted indirect comparison were similar. CONCLUSIONS: Population-adjusted indirect comparison suggests nivolumab±ipilimumab was more efficacious than SOC for 3L SCLC in terms of OS based on real-word data. An analysis using individual patient data from routine practice observational data to better account for between-study differences in patient characteristics is ongoing.