Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 09 2023
15 09 2023
Historique:
received:
25
02
2023
revised:
06
04
2023
accepted:
03
05
2023
pmc-release:
15
03
2024
medline:
18
9
2023
pubmed:
25
5
2023
entrez:
25
5
2023
Statut:
ppublish
Résumé
Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.
Identifiants
pubmed: 37227187
pii: 726931
doi: 10.1158/1078-0432.CCR-23-0536
pmc: PMC10524218
mid: NIHMS1900404
doi:
Substances chimiques
sacituzumab govitecan
M9BYU8XDQ6
berzosertib
L423PRV3V3
Camptothecin
XT3Z54Z28A
Immunoconjugates
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3603-3611Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC011793
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2023 American Association for Cancer Research.
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