Abstract 5305: Delta-like ligand 3 immunohistochemical expression landscape in high-grade lung neuroendocrine tumors
Authors: Lima Cibelle F. , Rocha Pedro S. , Fujimoto Junya , Stewart Allison , Cardnell Robert , Lu Wei , Khan Khaja , Sable Beate , Ellison Aaron R. , Wistuba Ignacio I. , Gay Carl M. , Kalhor Neda , Byers Lauren A. , Solis-Soto Luisa M. 
Published: June 2022

Abstract
Background: High-grade lung neuroendocrine tumors are a heterogeneous group of cancers with aggressive common features and a lack of effective therapeutic options. Recently, efforts have been made to identify new targets and drugs to improve clinical outcomes in these patients. Because of its high expression in neuroendocrine tumors compared to normal tissue, delta-like ligand 3 (DLL3) has emerged as a new therapeutic target in this setting.1,2 Targeting DLL3 with the half-life extended bispecific T cell engager (HLE BiTE®) immune therapy, tarlatamab, in a phase 1 clinical trial has demonstrated promising anti-tumor activity in small cell lung cancer (SCLC) patients.3 In order to more precisely guide patient selection and clinical trial design, a better understanding and quantification of DLL3 expression is required. Thus, we investigated DLL3 immunohistochemical expression across SCLC, large cell neuroendocrine carcinoma (LCNEC), and neuroendocrine carcinoma with combined histology (CNEC), and its associations with clinicopathological characteristics.
Design: Formalin-fixed and paraffin-embedded surgically resected lung neuroendocrine carcinomas (SCLC, n=17; LCNEC, n=20; CNEC, n=8) were selected based on tissue availability at MD Anderson Cancer Center and stained with a commercially available immunohistochemistry assay for DLL3 (clone SP347, Ventana). Total percentage and intensity of DLL3 expression of neuroendocrine carcinoma cells were scored and the results were presented as H-Score (0-300) and percentage (%) of DLL3 positive tumor cells. We correlated DLL3 expression with clinicopathological characteristics.
Results: DLL3 expression was observed in 37/45 (82%) of all cases (SCLC: %, median=65%, 0-100%; H-score, median=95, 0-175; LCNEC: %, median=65%, 0-100%; H-score, median=100, 0-180; CNEC: %, median=55%, 0-95%; H-score, median=90, 0-175). In patients with LCNEC, DLL3 % was higher in male patients (p=0.0500) and former smokers (p=0.0298) compared to females and current smokers, respectively. No other clinicopathological associations were found with age, Tumor-Node-Metastasis (TNM) staging system, recurrence, neoadjuvant therapy or overall survival.
Conclusion:Our work confirms that most high-grade neuroendocrine tumors express DLL3 across histology types and TNM stage. Our results suggest that a large subset of patients with high-grade lung neuroendocrine tumors may be a target population of interest for DLL3-targeted therapies.
References
1. Saunders LR, et al. Sci Transl Med. 2015;7(302):302ra136.
2. Alì G, et al. Front Oncol. 2021;11:729765.
3. Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4-8, 2021; Virtual.
Citation Format: Cibelle F. Lima, Pedro S. Rocha, Junya Fujimoto, Allison Stewart, Robert Cardnell, Wei Lu, Khaja Khan, Beate Sable, Aaron R. Ellison, Ignacio I. Wistuba, Carl M. Gay, Neda Kalhor, Lauren A. Byers, Luisa M. Solis-Soto. Delta-like ligand 3 immunohistochemical expression landscape in high-grade lung neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5305.