Circulating Tumor Cells Predict Response to the DLL3-targeting Bispecific Antibody Tarlatamab
Menée à l'aide d'échantillons sanguins et d'échantillons tumoraux prélevés sur 20 patients atteints d'un cancer du poumon à petites cellules traité par tarlatamab, cette étude met en évidence une association entre l'expression, avant traitement, du ligand DLL3 sur les cellules tumorales circulantes et la réponse thérapeutique
The bispecific antibody tarlatamab recruits T cells to cancers expressing the neuroendocrine epitope 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 (CTCs) 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, 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 neuro-endocrine 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.
Cancer Discovery , article en libre accès, 2026