Circulating Tumor Cells Predict Response to the DLL3-Targeting Bispecific Antibody Tarlatamab
Avanish Mishra1,2,3, Catherine B Meador4, Kruthika Kikkeri1,2,3,5
1Center for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Cancer Discovery
|January 14, 2026
Summary
Tarlatamab shows promise for small cell lung cancer (SCLC) by targeting DLL3. Measuring DLL3 on circulating tumor cells (CTCs) can predict patient response and guide treatment decisions for this cancer therapy.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Discovery
Background:
- Tarlatamab, a bispecific antibody, targets the DLL3 neuroendocrine epitope to engage T cells against cancer.
- Small cell lung cancer (SCLC) shows variable responses to tarlatamab, necessitating patient selection biomarkers.
Purpose of the Study:
- To identify biomarkers for predicting tarlatamab efficacy in SCLC patients.
- To investigate mechanisms of response and acquired resistance to tarlatamab therapy.
Main Methods:
- Single-cell RNA sequencing of SCLC biopsies to assess DLL3 heterogeneity.
- Analysis of circulating tumor cells (CTCs) for DLL3 expression levels (DLL3Pos vs. DLL3Low).
- Prospective cohort study of 20 patients to validate DLL3-positive CTCs as a predictive biomarker.
Main Results:
- Pretreatment DLL3 expression on CTCs accurately predicts tarlatamab clinical benefit (85% sensitivity, 100% specificity).
- Necrotic CTC clusters in blood correlate with treatment-induced tumor lysis.
- Acquired resistance mechanisms include loss of DLL3 expression or T cell dysfunction despite DLL3 retention.
Conclusions:
- Quantifying DLL3-positive CTCs identifies SCLC patients likely to benefit from tarlatamab.
- Longitudinal monitoring of CTCs can inform therapeutic adjustments during acquired resistance.
- DLL3-positive CTCs serve as a predictive and monitoring biomarker for tarlatamab therapy in SCLC.
