Background: Lurbinectedin monotherapy is currently approved for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy based on the results of a single-arm phase 2 basket trial. The current study established real-world comparator arms (RWCAs) to enable retrospective comparison of the efficacy of lurbinectedin from the trial, notably overall survival (OS) and overall response rate (ORR), to other standard of care treatments. Methods: This exploratory study consisted of two arms, where the 1^st arm was the lurbinectedin trial arm (LTA) comprised of data from the SCLC cohort of the trial (NCT02454972) and the 2^nd arm was an RWCA sourced from ConcertAI electronic medical records in the US (2010 to 2019). Relevant inclusion and exclusion criteria from the trial were applied to the RWCA to ensure comparability at baseline. Given the absence of Eastern Cooperative Oncology Group performance status (ECOG) for a sizable portion of patients in the RWCA, two RWCA groups were studied, one that excluded patients with reported ECOG > 2 (RWCA1) and the other that excluded patients with reported ECOG > 2 and missing ECOG (RWCA2). Propensity score (PS) weighting was used to further balance measured baseline characteristics between LTA and each RWCA. OS was defined as the time from treatment initiation to death. Weighted cox regression was used to compare OS. ORR was defined as the percentage of patients with a complete or partial response. A weighted two-sample test of proportions was used to compare ORR. Results: This study included 105 patients in LTA and 121 in RWCA1 (74 in RWCA2). After PS weighting, baseline characteristics were mostly similar between LTA and each RWCA. ECOG was balanced between RWCA2 and LTA but was different between RWCA1 and LTA. A numerical median OS benefit of 3.8 and 4.7 months was observed in LTA, compared to RWCA1 and RWCA2, respectively (see table). Probability of survival was greater in LTA compared to RWCAs at 3 and 6 months. ORR was two-fold higher in LTA compared to RWCA1. Consistent findings were seen for LTA compared to RWCA2. Conclusions: Lurbinectedin monotherapy demonstrated improved median OS, lower risk of death at 3 and 6 months, and higher response rate compared to other standard of care treatments in relapsed/refractory SCLC. Future studies with larger sample size powered to detect statistical differences in OS are warranted.