Circulating Tumor Cells Predict Response to the DLL3-Targeting Bispecific Antibody Tarlatamab

The bispecific antibody tarlatamab recruits T cells to cancers expressing the neuroendocrine epitope delta-like ligand 3 (DLL3). Tarlatamab is effective in small cell lung cancer (SCLC), but clinical outcomes vary, and no biomarkers enable patient selection. Single-cell RNA sequencing of SCLC biopsies identifies heterogeneity in DLL3 expression, and analysis of circulating tumor cells (CTC) distinguishes individual patients as predominantly DLL3Pos or DLL3Low. In a prospective cohort of 20 patients, pretreatment DLL3 expression on CTCs predicts tarlatamab clinical benefit (85% sensitivity and 100% specificity). Necrotic CTC clusters in blood accompany treatment-induced tumor lysis. Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression but persistence of other targetable neuroendocrine epitopes; in other patients, DLL3 is retained on CTCs but accompanied by systemic markers of T-cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance. SIGNIFICANCE: CTCs are abundant in SCLC, allowing noninvasive quantitation of epitopes targeted by immune therapies. Patients with at least 25% DLL3-positive CTCs derive clinical benefit from a bispecific antibody targeting this epitope; those with a lower fraction rarely respond. CTC scoring may thus enable stratification of patients for antibody-mediated therapeutics.