50P DLL3 expression by immunohistochemistry in rare neuroendocrine neoplasms and associated response to off label tarlatamab

This retrospective multicenter cohort study evaluated the efficacy and safety of tarlatamab, a DLL3-directed bispecific T-cell engager approved for relapsed small cell lung cancer, in 13 heavily pretreated patients with rare neuroendocrine neoplasms beyond small cell lung cancer across five academic centers. Among evaluable patients, the objective response rate was 54.5%, with responses observed across a diverse range of tumor types including large cell neuroendocrine carcinoma and extrapulmonary small cell carcinomas of the bladder, esophageal, anal, and laryngeal origins. DLL3 expression was high across the cohort, with 87.5% of tested tumors showing positivity, and antitumor activity was observed at the site of DLL3-positive biopsy in 83.3% of responding patients. Notably, tarlatamab was well tolerated, with only one case of grade 3 or higher cytokine release syndrome.

These findings suggest that DLL3 expression may serve as a meaningful precision medicine target well beyond small cell lung cancer, opening a potential new treatment avenue for patients with rare neuroendocrine neoplasms who have limited options after prior therapies. The study underscores the importance of standardized DLL3 testing across tumor types and supports the case for prospective trials to confirm tarlatamab's efficacy and optimal patient selection in this broader population.