Circulating Tumor Cells Predict Response to the DLL3-Targeting Bispecific Antibody Tarlatamab
Avanish Mishra, Catherine B. Meador, Kruthika Kikkeri, Quinn E. Cunneely, Maoxuan Lin, Thomas J. Carmona-LaSalle, S.H. Huang, Remy Bell, Victor R. Putaturo, Weikun Xia, Joyce Liang, Jacy Fang, Sarah San Vicente, Caroline Zielinski, Subba R. Digumarthy, Yin P. Hung, Beow Y. Yeap, Jon F. Edd, Michael S. Lawrence, Moshe Sade-Feldman, Debattama R. Sen, Mehmet Toner, Shyamala Maheswaran, Justin F. Gainor, Daniel A. Haber
Abstract
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.