DLL3 on circulating tumor cells predicts tarlatamab success in lung cancer

A team led by investigators at the Mass General Brigham Cancer Institute has discovered that a particular marker on tumor cells circulating in the blood indicates whether a patient with lung cancer will experience a lasting response to a newly approved immunotherapy called tarlatamab. The findings, which are published in Cancer Discovery, could allow clinicians to easily and noninvasively determine which patients should receive the drug.

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 tumor cells. 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."

Daniel A. Haber, MD, PhD, senior and co-corresponding author, director of the Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute

The blood cell enrichment technology has been licensed to TellBio, Inc.

The study focused on whether properties of circulating tumor cells might correlate with a patient's response to tarlatamab, which was fully approved in late 2025 as a treatment for small cell lung cancer (SCLC) after prior chemotherapy. Tarlatamab is an antibody that recruits T cells to cancer cells expressing a specific neuro-endocrine marker called DLL3.

Although tarlatamab showed promise in clinical trials, about half of patients with SCLC experience cancer progression within six months of initiating therapy. It was thought that every SCLC case expresses DLL3, but Haber and colleagues found that only half of the 20 patients they studied had abundant DLL3-positive cancer cells in their blood, and these were the patients who responded to tarlatamab. DLL3 testing on CTCs correctly identified 85% of patients who had a clinical benefit from the drug and 100% who did not (85% sensitivity, 100% specificity).

The study, which was a collaboration between bioengineering experts who had developed the technology to analyze rare cancer cells in blood specimens, and lung cancer clinicians, has important implications for clinical care.

"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 co-corresponding author Justin Gainor, MD, program director of the Center for Thoracic Cancers at the Mass General Brigham Cancer Institute. "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."