DLL3-targeted therapy with tarlatamab in small cell lung cancer across lines of therapy: A systematic review of prospective and randomized clinical trials.

e14525 Background: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options beyond first-line therapy. Delta-like ligand 3 (DLL3) is highly expressed on SCLC tumor cells and is a rational target. Tarlatamab is a first-in-class DLL3-directed bispecific T-cell engager that has demonstrated clinical activity in prospective trials and has received regulatory approval for extensive-stage SCLC. While early-phase studies established activity in previously treated disease, subsequent trials have expanded its relevance into earlier treatment lines. We conducted a systematic review of prospective clinical trials to synthesize the efficacy and safety of tarlatamab. Methods: A systematic literature review was performed in accordance with PRISMA. PubMed, Embase, and major oncology conference proceedings (ASCO, ESMO, AACR) were searched from inception through January 2026 using the terms “tarlatamab,” “DLL3,” “DeLLphi,” and “small-cell lung cancer.” Eligible studies included prospective phase I–III trials evaluating tarlatamab alone or combination regimens. Outcomes included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS) and neurologic toxicity. Phase III data were included for contextual relevance but were not pooled with early-phase efficacy outcomes. Results: Prospective evidence included DeLLphi-300 (phase I) and DeLLphi-301 (phase II) monotherapy trials in previously treated SCLC, and phase III trials DeLLphi-304 and DeLLphi-305 evaluating earlier-line strategies. In DeLLphi-301, FDA-reported efficacy included ORR 40% (95% CI, 31–51), median DOR 9.7 months (range, 2.7–20.7+), median PFS 4.9 months in the 10-mg cohort, CRS in approximately 51% (10 mg) and 61% (100 mg) of patients, predominantly grade 1–2. DeLLphi-300 demonstrated activity in heavily pretreated SCLC (ORR ~23–35% across dose cohorts), supporting proof-of-concept for DLL3-directed T-cell redirection. DeLLphi-304 compared tarlatamab monotherapy with standard-of-care chemotherapy in patients progressing on or after one line of platinum-based therapy, met its primary endpoint with a statistically significant OS improvement at interim analysis. DeLLphi-305 is an ongoing randomized phase III study evaluating tarlatamab plus durvalumab versus durvalumab alone as first-line maintenance therapy. Conclusions: Across prospective trials, tarlatamab demonstrates clinically meaningful activity in extensive-stage SCLC with a manageable safety profile characterized by predominantly low-grade CRS and infrequent severe CRS/ICANS with step-up dosing. Early-phase data support its approved use after platinum progression, while emerging phase III evidence suggests potential benefit in earlier treatment settings.