Clinicopathological Features of DLL3 Expression and T-Cell Infiltration in LCNEC: Insights From Pathology and Clinical Response to Tarlatamab.

BACKGROUND

Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive lung neuroendocrine neoplasm with poor prognosis. Recently, DLL3-targeted bispecific T-cell engagers (BiTEs) have shown promising efficacy in small cell lung cancer, and clinical trials are ongoing in LCNEC. This study evaluated DLL3 expression and CD8+ tumor-infiltrating lymphocytes (TILs) infiltration in LCNEC and investigated their clinical significance and association with tarlatamab efficacy.

METHODS

We retrospectively reviewed consecutive patients who were diagnosed with LCNEC. Immunohistochemical analyses for DLL3 and CD8 were performed. DLL3 positivity was defined as staining in ≥ 1% of tumor cells. CD8+ TIL infiltration was graded as low, moderate, or high.

RESULTS

Among 77 screened LCNEC cases, 44 were eligible for analysis. The median age was 75 years. DLL3 expression was observed in 70.5% of cases and was associated with worse survival. Low CD8+ TIL infiltration was observed in 59.1% of cases. Patients with high CD8+ TIL infiltration demonstrated significantly longer survival than those with low infiltration (p = 0.03). Among representative clinical cases, a patient with DLL3 (+)/CD8 TILs (-) LCNEC achieved marked tumor shrinkage, whereas a patient with DLL3 (-)/CD8 TILs (-) LCNEC showed no response.

CONCLUSIONS

DLL3 is frequently expressed in LCNEC and correlates with a poorer prognosis. A majority of LCNEC cases are immunologically characterized as cold tumors lacking CD8+ TILs, which contributes to unfavorable clinical outcomes. Tarlatamab induced a robust antitumor response even in a DLL3 (+) cold tumor. DLL3-BiTE represents a promising therapeutic strategy for DLL3 (+) LCNEC.