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Background Small cell lung cancer (SCLC) is an aggressive form of neuroendocrine cancer that have a poor prognosis with limited treatment options. Tarlatamab is a first-in-class, half-life extended delta-like ligand 3 (DLL3) directed bispecific T-cell engager (BiTE®) immunotherapy that has shown clinical efficacy in SCLC patients with previously treated with chemoimmunotherapy. However, the duration of treatment response is short, and the majority of patients develop resistance to tarlatamab. The biomarker and mechanistic studies are limited by lack of tumor specimens from patients with metastatic SCLC. The objective of this study is to determine predictive biomarkers and resistance mechanisms to tarlatamab treatment using blood samples collected from patients receiving tarlatamab treatment.Methods We developed a pragmatical protocol to allow serial collection of blood samples and chart review for SCLC patients receiving standard of care tarlatamab at our institution. We analyze the clinic, demographics, radiographic, and laboratory data in the electronic medical records for correlation with tarlatamab treatment. We plan to perform immunophenotyping of peripheral mononuclear blood cells (PBMCs) and serum biomarker assays using established multicolor spectral flow cytometry, RNA sequencing and cytokine assays for predictive biomarkers and primary and acquired resistance mechanisms using these blood samples.Results This is the first report of 13 patients received tarlatamab treatment. Median age (range): 67 (45-78) years old. Male: 7%57%). White/Asian/Black/Hispanic/Other: 7/3/1/1/1. CRS: grade 1/2/3/4: 2/3/1/0. ICANS: grade 1/2/3/4: 1/0/0/0. Eleven out of 12 patients had mixed tumor responses and 1 patient is in cycle 1 treatment. We observed that tarlatamab treatment resulted in a rapid increase in absolute lymphocyte count (ALC). Those patients who maintained high ALCs throughout subsequent cycles of tarlatamab had good clinical response to tarlatamab ( figure 1). Lack of increased ALC number post-tarlatamab treatment correlates with poor clinical response. Immunophenotyping of serial PBMCs revealed that tarlatamab treatment increased the number of total CD3+ T cells, cytotoxic CD8+ T cells and CD19+ B cells, and decreased the number of CD4+ T cells and CD56+NK cells (figure 2). Ongoing studies are collecting more patient samples and analyzing the data for resistance mechanisms.Conclusions Preliminary data show that it is feasible to collect and analyze blood-based biomarkers from patients receiving tarlatamab treatment. Further studies are warranted to gain insight of resistance mechanisms and validate predictive biomarkers for tarlatamab.Abstract 565 Figure 1Changes of blood biomarker ALC in SCLC patients treated with Tarlatamab. Different colors annotate different patients receiving tarlatamab. Rapid increase in ALCs that are maintained above 400 after treatment correlate with good clinical response. ALC: absolute lymphocyte count (cells/uL). SCLC: small cell lung cancer. C1D1: Treatment Cycle 1 day 1 (1 cycle is 4 weeks)Abstract 565 Figure 2Immunophenotyping of circulating blood immune cells by multicolor spectral flow cytometry. Multicolor flow cytometry analysis of serial PBMCs showing tarlatamab treatment increased the number of total CD3+ T cells, cytotoxic CD8+ T cells and CD19+ B cells, and decreased the number of CD4+ T cells and CD56+NK cells