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Open Access 24-06-2023 | SCLC | Review

Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer

Authors: Charles M. Rudin, Martin Reck, Melissa L. Johnson, Fiona Blackhall, Christine L. Hann, James Chih-Hsin Yang, Julie M. Bailis, Gwyn Bebb, Amanda Goldrick, John Umejiego, Luis Paz-Ares

Published in: Journal of Hematology & Oncology | Issue 1/2023

Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules—tarlatamab (formerly known as AMG 757), BI 764532, and HPN328—and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

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Title: Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer
Authors: Charles M. Rudin
Martin Reck
Melissa L. Johnson
Fiona Blackhall
Christine L. Hann
James Chih-Hsin Yang
Julie M. Bailis
Gwyn Bebb
Amanda Goldrick
John Umejiego
Luis Paz-Ares
Publication date: 24-06-2023
Publisher: BioMed Central
Keywords: SCLC
Targeted Therapy
Thoracic Cancer
Respiratory Medicine
SCLC
Lung Cancer
Lung Cancer
Lung Cancer
Published in: Journal of Hematology & Oncology / Issue 1/2023
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-023-01464-y

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