Circulating Tumor Cells May Guide Use of Tarlatamab in Small Cell Lung Cancer

New research published in Cancer Discovery suggests that circulating tumor cells (CTCs) in the blood may help identify which patients are most likely to experience a durable response to tarlatamab (Imdelltra; Amgen), potentially offering health care professionals a noninvasive tool to personalize treatment decisions.^1,2

Tarlatamab is the first-in-class bispecific T cell engager with dual specificity for delta-like ligand 3 (DLL3) and CD3, targeting a neuroendocrine antigen that is excessively expressed in tumor cells of small cell lung cancer (SCLC) compared with normal adult tissues. Tarlatamab binds to DLL3 overexpressed on tumor cells and CD3+ immune cells, redirecting immune cells to destroy tumor cells. This therapy gained full approval by the FDA in late 2025, based on clinical trials demonstrating signs of response in patients with SCLC who were treated with tarlatamab following chemotherapy.^3,4

Despite this progress, about half of patients treated for SCLC have experienced progression of disease after 6 months of initiating tarlatamab. The outcome has raised several concerns about whether only expression of DLL3 is universal in patients suffering from SCLC or not. Traditional tissue biopsies can be invasive, difficult to repeat, and may not fully capture tumor heterogeneity, particularly in an aggressive disease such as SCLC. These limitations have driven interest in blood-based biomarkers, including CTCs.

Circulating Tumor Cells as a Noninvasive Biomarker

This study, which was led by investigators at Mass General Brigham Cancer Institute, evaluated the potential for characteristics of CTCs to predict the response to tarlatamab therapy. In collaboration with a patented blood cell enrichment platform developed via bioengineering advancements, researchers analyzed the blood of 20 patients with SCLC undergoing tarlatamab therapy.¹

Contrary to prior assumptions that all SCLC tumors express DLL3, the investigators found that only about half of the patients had abundant DLL3-positive CTCs in their bloodstream; however, these are the patients who saw a significant improvement with tarlatamab. DLL3 testing on CTCs correctly identified 85% of patients who responded to therapy, and 100% of those who did not, corresponding to 85% sensitivity and 100% specificity.¹

“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,” said Daniel A. Haber, MD, PhD, senior and cocorresponding author and director of the Krantz Family Center for Cancer Research at the Mass General Brigham Cancer Institute. “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.”²

Clinical Implications for Pharmacists and Care Teams

These findings may have important implications for oncology pharmacists, who play a vital role in treatment optimization, patient education, and interdisciplinary care coordination. A validated blood-based assay for DLL3-positive CTCs could help clinicians avoid exposing patients to therapies unlikely to benefit them, reducing unnecessary toxicity, treatment delays, and health care costs.

As far as medication management is concerned, tarlatamab causes immune-related reactions such as cytokine release syndrome and neurological symptoms, among others, that have to be properly monitored.³ It would be helpful to be able to determine which patients would most likely benefit from the therapy so that such risks may be properly offset. Additionally, pharmacists can be involved in informing patients regarding the reason behind such decisions related to biomarkers, especially with the integration of blood-based diagnostics in cancer treatment.

Broader Implications for DLL3-Targeted Therapies

Beyond tarlatamab, the study’s findings may influence the broader field of DLL3-targeted therapies, many of which are currently in development. According to Justin Gainor, MD, program director of the Center for Thoracic Cancers at the Mass General Brigham Cancer Institute and co-corresponding author, the implications extend beyond a single drug. “Our work may help predict which patients with SCLC are likely to respond to tarlatamab and potentially other antibodies targeting DLL3,” Gainor said. “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.”²

DLL3 expression has been observed in other high-grade neuroendocrine tumors, raising the possibility that similar CTC-based strategies could be applied across multiple malignancies as antibody-directed therapies expand.^1,5

Conclusion

SCLC is one of the most aggressive types of cancer, with rapid proliferation, rapid metastasis, and a very limited therapeutic regimen for long-term management. Despite high sensitivity to the therapeutic effects of chemotherapy, relapse is very common among patients with SCLC, with very low overall survival. Recently, the emergence of tarlatamab, a DLL3-targeting bispecific antibody, brought a beacon of hope to SCLC patients during relapse, but clinic experiences have proven that not all SCLC patients can benefit from this medication.

REFERENCES

1. Mishra A, Meador CB, Kruthika Kikkeri, et al. Circulating Tumor Cells Predict Response to the DLL3-targeting Bispecific Antibody Tarlatamab. Cancer Discovery. Published online January 14, 2026. doi:10.1158/2159-8290.cd-25-1483
2. Blood Test Predicts Which Patients with Lung Cancer Will Benefit from Newly Approved Immunotherapy Drug. Mass General Brigham. Published January 14, 2026. Accessed January 16, 2026. https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/blood-test-predicts-benefit-from-tarlatamab
3. McGovern G. FDA Approves Tarlatamab-Dlle to Treat Adults With Extensive Stage Small Cell Lung Cancer. Pharmacy Times. Published November 19, 2025. Accessed January 16, 2026. https://www.pharmacytimes.com/view/fda-approves-tarlatamab-dlle-to-treat-adults-with-extensive-stage-small-cell-lung-cancer
4. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer. Published 2025. Accessed January 16, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
5. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. doi:10.1126/scitranslmed.aac9459