Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer Review
| Authors: | Rudin, C. M.; Reck, M.; Johnson, M. L.; Blackhall, F.; Hann, C. L.; Yang, J. C. H.; Bailis, J. M.; Bebb, G.; Goldrick, A.; Umejiego, J.; Paz-Ares, L. |
| Review Title: | Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer |
| 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. © 2023, The Author(s). |
| Keywords: | cancer survival; survival rate; unclassified drug; overall survival; drug tolerability; fatigue; neutropenia; review; cancer recurrence; dose response; drug efficacy; drug safety; monotherapy; nonhuman; patient selection; drug targeting; neurotoxicity; clinical practice; cd8+ t lymphocyte; biological marker; metabolism; cancer immunotherapy; progression free survival; neoplasm recurrence, local; nausea; thrombocytopenia; lung neoplasms; membrane proteins; antineoplastic activity; tumor regression; prediction; dizziness; fever; pneumonia; health care quality; lung tumor; cancer inhibition; confusion; hypotension; maculopapular rash; clinical study; drug mechanism; tumor recurrence; signal peptide; intracellular signaling peptides and proteins; cd4+ t lymphocyte; membrane protein; ligand; brain disease; ligands; pleura effusion; headache; drug cytotoxicity; drug half life; cancer classification; pericardial effusion; neurologic disease; disease exacerbation; dysgeusia; neuroendocrine carcinoma; small cell lung cancer; drug indication; small cell lung carcinoma; phase 2 clinical trial (topic); phase 3 clinical trial (topic); phase 1 clinical trial (topic); cancer prognosis; antibody-drug conjugate; blinatumomab; humans; human; bite; dll3; rovalpituzumab tesirine; antibody drug conjugate; chimeric antigen receptor immunotherapy; chimeric antigen receptor natural killer cell immunotherapy; mosunetuzumab; teclistamab; dll3 protein, human; amg 757; t-cell engager; tarlatamab; amg 119; bi 764532; delta like ligand 3; hpn 328; t cell engager molecule |
| Journal Title: | Journal of Hematology & Oncology |
| Volume: | 16 |
| ISSN: | 1756-8722 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2023-06-24 |
| Start Page: | 66 |
| Language: | English |
| DOI: | 10.1186/s13045-023-01464-y |
| PUBMED: | 37355629 |
| PROVIDER: | scopus |
| PMCID: | PMC10290806 |
| DOI/URL: | |
| Notes: | Review -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Charles Rudin -- Source: Scopus |
