8100 Background: Extensive stage small cell lung cancer is an aggressive malignancy with rapid progression and poor survival after relapse following platinum-based chemotherapy. Tarlatamab, a DLL3 directed bispecific T cell engager, demonstrated a significant overall survival benefit compared with physician’s choice of chemotherapy, including lurbinectedin, in the phase 3 DeLLphi 304 trial. However, access to tarlatamab remains limited in routine clinical practice, and lurbinectedin continues to be commonly used in the post platinum setting. As a result, real world data comparing the effectiveness and toxicity of these agents are needed to better inform treatment decisions for patients with relapsed small cell lung cancer. Methods: We conducted a retrospective cohort study using the TriNetX Research Network, a federated, de-identified electronic health record database. Adults with lung cancer who received platinum-based chemotherapy or immunotherapy as first-line treatment and subsequently initiated tarlatamab or lurbinectedin as second-line therapy between January 1, 2020 and November 1, 2025 were included. Propensity score matching was then performed and overall survival was evaluated using Kaplan–Meier methods. Secondary outcomes included immune- and treatment-related adverse events, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS/ICE), and corticosteroid use. Results: After 1:1 propensity score matching, both groups had 133 patients each with good balance across demographics, comorbidities, metastatic burden, prior therapies, and baseline laboratory. At 1 year, mortality was 33.1% with tarlatamab versus 72.2% with lurbinectedin (absolute risk reduction 39.1%, 95% CI 28.1–50.1; p < 0.0001), with improved 1-year survival probability (59.2% vs 17.1%) and superior overall survival (HR 0.46, 95% CI 0.32–0.66; log-rank p < 0.0001). The survival benefit persisted at 2 years, with median survival of 417 days versus 149 days and survival probabilities of 47.4% versus 15.9%, respectively (HR 0.48, 95% CI 0.34–0.68; p = 0.0015). Tarlatamab was associated with higher corticosteroid use (56.4% vs 33.8%, p = 0.0002) and immune-mediated toxicities, including cytokine release syndrome in 45.1% (grade 1: 23.3%, grade 2: 13.5%) and ICANS/ICE in 17.3%, with no grade 4–5 events. Conclusions: In this propensity score–matched analysis, tarlatamab demonstrated a significant and durable overall survival advantage over lurbinectedin, with an approximately 50% relative reduction in the risk of death at both 1 and 2 years based on hazard ratios. While tarlatamab was associated with higher rates of expected immune-mediated toxicities, including CRS and ICANS, events were predominantly low-grade, supporting a favorable benefit–risk profile in this heavily pretreated metastatic population.
Khan et al. (Thu,) studied this question.