Tarlatamab Resistance in Small Cell Lung Cancer Linked to DLL3 Downregulation and Immune Exhaustion

Clinical Summary:

• Design/Population: A case-based translational analysis evaluated paired tumor biopsies from 2 patients with extensive-stage small cell lung cancer treated with tarlatamab plus anti-PD-1 therapy, analyzing baseline and progression samples using multiplex immunohistochemistry.
• Key Outcomes: At progression, tumors showed reduced DLL3 expression and a phenotypic shift with loss of neuroendocrine markers, suggesting antigen escape. The tumor microenvironment demonstrated increased exhausted CD8+ T cells and enrichment of immunosuppressive cells.
• Clinical Relevance: Resistance to tarlatamab may be driven by target antigen loss and an immunosuppressive microenvironment, supporting development of combination strategies to overcome resistance in small cell lung cancer.

Results from a case-based translational analysis indicate that acquired resistance to tarlatamab among patients with extensive-stage small cell lung cancer (SCLC) may be driven by tumor antigen loss and tumor microenvironment changes. 

“Tarlatamab, a bispecific T-cell engager that targets CD3 and [DLL3), is the standard of care for patients with previously treated SCLC… however, the mechanisms underlying acquired tarlatamab resistance remain unclear,” stated Akito Fukuda, MD, National Cancer Center Hospital, Tokyo, Japan, and coauthors.

In this study, researchers evaluated tumor samples from 2 patients with extensive-stage SCLC who received tarlatamab plus an anti-PD-1 antibody in a phase 1b trial. Paired biopsies obtained at baseline and at disease progression were analyzed using multiplex immunohistochemistry to assess tumor phenotype and immune contexture. 

At progression, both patients demonstrated a phenotypic shift in tumor morphology, with reduced neuroendocrine features, including decreased synaptophysin expression. Tumor cells also exhibited low DLL3 expression, the primary target of tarlatamab, suggesting antigen loss as a key resistance mechanism. There was enrichment of exhausted CD8+ T cells expressing PD-1, T-cell immunoreceptor with Ig and ITIM domains, and lymphocyte-activation gene 3. There were also increased infiltration of immunosuppressive cell populations, including cytotoxic T-lymphocyte-associated protein 4 regulatory T cells and CD206+ M2 tumor-associated macrophages. 

“Acquired resistance to tarlatamab plus anti-PD-1 in SCLC was associated with low DLL3 antigen expression particularly in the setting of phenotypic switch to an NSCLC morphology and an increasingly immunosuppressive tumor microenvironment,” concluded Dr Fukuda et al. “Combination strategies that incorporate immune checkpoint blockade or myeloid-targeted therapies may be warranted to enhance treatment outcomes.” 

Source:

Fukuda A, Fukami T, Nomura K, et al. Brief Report: Low delta-like ligand 3 expression and T-cell exhaustion drive resistance to tarlatamab combined with anti–programmed cell death protein 1 in SCLC. J Thorac Oncol. Published online: March 26, 2026. doi:10.1016/j.jtho.2026.103693