Real-World Effectiveness and Safety of Tarlatamab in Small Cell Lung Cancer: A Systematic Review

Background: Tarlatamab, a delta-like ligand 3 (DLL3)-targeted bispecific T-cell engager, has demonstrated clinical efficacy in previously treated small cell lung cancer (SCLC). However, its effectiveness and safety in routine clinical practice, particularly among patients underrepresented in clinical trials, remain incompletely characterized. Objective: To systematically review available real-world evidence regarding the effectiveness and safety of tarlatamab in patients with SCLC. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420261345046). PubMed, the Cochrane Library, and ScienceDirect were searched for observational studies reporting real-world effectiveness or safety outcomes. Of 141 identified records, 134 remained after duplicate removal, and five retrospective studies met the eligibility criteria. Study characteristics, effectiveness outcomes, and adverse events were synthesized narratively because of heterogeneity in patient populations, outcome definitions, and follow-up. Results: Five retrospective real-world studies were included. Reported partial or objective response proportions ranged from 35.2% to 66.7% across selected predominantly de novo SCLC cohorts, with estimates frequently restricted to response-evaluable subsets. The EGFR-mutant transformed SCLC cohort was analyzed separately. In one cohort, the reported objective response rate was 66.7% (20/30), corresponding to documented responses in 41.7% (20/48) of all treated patients. Median progression-free survival ranged from 1.7 to 4.9 months across reported analyses. Patients with EGFR-mutant transformed SCLC demonstrated less favorable outcomes, with partial response in 7.1% (1/14) of response-evaluable patients and median overall survival of 2.7 months. Cytokine release syndrome occurred in 54.2–72.7% of patients in selected cohorts, while ICANS occurred in 23.3–47.6%, with substantial variation across study populations and treatment protocols. The overall certainty of evidence was very low. Conclusions: Available real-world evidence suggests that tarlatamab demonstrates clinically meaningful antitumor activity in previously treated SCLC, including patients with adverse baseline characteristics. However, effectiveness estimates are limited by small sample sizes, selection of response-evaluable populations, and heterogeneous outcome assessment. The relatively high incidence of ICANS reported in several real-world cohorts warrants particular attention, although differences in patient characteristics and toxicity ascertainment limit direct comparisons with clinical trials. Larger prospective studies are needed to establish real-world effectiveness and optimize toxicity management. Registration: CRD420261345046.