Blood test marker predicts response to tarlatamab in small cell lung cancer

Researchers at Mass General Brigham Cancer Institute have reported that measuring delta-like ligand 3 (DLL3) on circulating tumour cells in a simple blood sample may help clinicians to identify which patients with small cell lung cancer are likely to benefit from the recently approved immunotherapy tarlatamab

A blood-based test that detects a cell-surface marker on circulating tumour cells may help clinicians to predict which patients with small cell lung cancer (SCLC) will benefit from the immunotherapy tarlatamab, according to a study led by investigators at the Mass General Brigham Cancer Institute, Boston, Massachusetts, USA.

The findings linked the presence of delta-like ligand 3 (DLL3) on tumour cells circulating in the bloodstream with durable clinical response to tarlatamab, a bispecific antibody therapy that received traditional approval from the US Food and Drug Administration in November 2025 for extensive-stage small cell lung cancer with disease progression on or after platinum-based chemotherapy.

Circulating tumour cells are cancer cells that detach from tumours and enter the bloodstream. Although clinicians have long considered them a potential source of non-invasive information about tumour biology, their rarity in blood samples has made them difficult to isolate reliably and analyse at scale.

The Mass General Brigham team used a blood cell enrichment approach that enabled the capture and analysis of these scarce cells from patient specimens. The organisation has licensed the enrichment technology to TellBio, Inc.

“Isolating cancer cells from the blood has tremendous potential to guide immune-related cancer therapies, and our group has created cutting edge bioengineering technologies for purification of these circulating tumour cells,” said Dr. Daniel A. Haber, director of the Krantz Family Center for Cancer Research at the Mass General Brigham Cancer Institute and senior co-corresponding author of the study.

“We’ve learned a lot about the biology of these cells but we haven’t had a test that has direct clinical relevance. In this study, we believe that we achieved this,” he said.

The researchers set out to address a practical clinical problem with small cell lung cancer is an aggressive neuroendocrine malignancy that often responds initially to chemotherapy but frequently relapses rapidly. The emergence of immunotherapies and targeted immune therapies has offered additional options, yet clinicians still lack robust, widely available biomarkers to match patients to the treatments most likely to help them.

Tarlatamab acts by recruiting cytotoxic T cells towards cancer cells that express DLL3, a protein found on the surface of many small cell lung cancers. As a bispecific therapy, it binds to DLL3 on tumour cells and to CD3 on T cells, bringing the immune cells into close proximity to tumours and prompting immune-mediated killing. Clinical trial results have shown that some patients experience deep and durable responses – but outcomes vary substantially – with a sizeable fraction of patients experiencing disease progression within months of starting treatment.

The study tested whether DLL3 expression on circulating tumour cells could serve as a real-time indicator of treatment susceptibility. Although DLL3 expression has often been described as common in small cell lung cancer, the investigators reported that expression in blood-borne tumour cells was not universal in their patient cohort.

In a group of 20 patients with small cell lung cancer treated with tarlatamab, only around half had abundant DLL3-positive circulating tumour cells in blood specimens, and these were the patients who went on to show clinical benefit from the therapy.

By contrast, patients whose circulating tumour cells showed low DLL3 expression did not appear to derive meaningful benefit, suggesting that DLL3 detection in blood could help to guide treatment decisions.

On test performance, the team reported that DLL3 assessment in circulating tumour cells correctly identified 85% of patients who experienced clinical benefit from tarlatamab and 100% of patients who did not, corresponding to 85% sensitivity and 100% specificity within the studied cohort.

The researchers framed the work as a collaboration between bioengineering specialists who developed tools to isolate rare cancer cells from blood samples and thoracic oncology clinicians who treat small cell lung cancer. Together, they argued, this approach could shift patient selection away from assumptions about tumour-marker prevalence and towards direct measurement of treatment-relevant biology.

“Our work may help predict which patients with SCLC are likely to respond to tarlatamab and potentially other antibodies targeting DLL3, many of which are in development,” said Dr. Justin Gainor, programme director of the Center for Thoracic Cancers at the Mass General Brigham Cancer Institute and co-corresponding author of the study.

“It also has potential implications for other cancers that express DLL3 as they become more aggressive and for the field of antibody-directed cancer therapies,” he added.

Beyond tarlatamab, the authors suggested that a blood-based DLL3 readout could support the wider pipeline of DLL3-directed strategies, including additional bispecific antibodies and other antibody-based platforms. If validated in larger studies, the approach could offer a practical advantage for clinicians, because blood sampling is simpler, less invasive and easier to repeat than tissue biopsy. Serial blood testing could also enable clinicians to track changes in tumour phenotype during therapy, such as the emergence of DLL3-low subclones that escape immune pressure.

The study also highlighted a broader trend in oncology through efforts to move biomarker testing from static, one-off tumour sampling towards real-time monitoring using liquid biopsy. Compared with tumour tissue collected at diagnosis, circulating tumour cells can provide a contemporaneous view of disease biology during relapse and treatment, when decision-making becomes at its most urgent.

In this study the patient cohort was small, however, with the reported performance metrics require confirmation in larger, independent studies that capture the diversity of SCLC biology and treatment histories. In routine practice, further work will also be needed to standardise sample processing, define robust thresholds for DLL3 positivity, and establish how the assay performs across different clinical settings.

If subsequent trials validate these findings, DLL3 measurement on circulating tumour cells could become a useful tool to select patients for tarlatamab, while sparing non-responders from avoidable toxicity and delay, and therefore help clinicians to consider alternative regimens sooner in case of aggressive cancers.

For further reading please visit: 10.1158/2159-8290.CD-25-1483