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.
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.
Insights
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.
