Brief Report: Low Delta-Like Ligand 3 Expression and T-Cell Exhaustion Drive Resistance to Tarlatamab Combined With...

SCLC is an aggressive malignancy with poor prognosis. Tarlatamab, a bispecific T-cell engager that targets CD3 and delta-like ligand 3 (DLL3), is the standard of care for patients with previously treated SCLC. However, the mechanisms underlying acquired tarlatamab resistance remain unclear.

We assessed two patients with extensive-stage SCLC treated with tarlatamab and an anti-programmed cell death protein 1 (PD-1) antibody in a phase 1b clinical trial (jRCT: 2051240045). We analyzed tumor biopsy samples obtained at baseline and at time of progressive disease using multiplexed immunohistochemistry.

Pathologic analysis of post-resistance specimens revealed a phenotypic shift in both cases, characterized by tumor cells with abundant cytoplasm and reduced synaptophysin expression levels. Multiplexed immunohistochemistry revealed low DLL3 expression on tumor cells at time of progression. In addition, exhausted CD8⁺ T cells expressing PD-1⁺, T-cell immunoreceptor with Ig and ITIM domains, lymphocyte-activation gene 3, and immunosuppressive cells, including cytotoxic T-lymphocyte-associated protein 4 regulatory T cells and CD206⁺ M2 tumor-associated macrophages, were significantly more abundant in the tumor microenvironment than that in samples obtained before tarlatamab plus anti-PD-1 combination therapy.

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. Therefore, combination strategies that incorporate immune checkpoint blockade or myeloid-targeted therapies may be warranted to enhance treatment outcomes.