TY - JOUR
T1 - Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib
T2 - A Phase I Clinical Trial
AU - Abel, Melissa L.
AU - Takahashi, Nobuyuki
AU - Peer, Cody
AU - Redon, Christophe E.
AU - Nichols, Samantha
AU - Vilimas, Rasa
AU - Lee, Min -Jung
AU - Lee, Sunmin
AU - Shelat, Meenakshi
AU - Kattappuram, Robbie
AU - Sciuto, Linda
AU - Pinkiert, Danielle
AU - Graham, Chante
AU - Butcher, Donna
AU - Karim, Baktiar
AU - Sharma, Ajit Kumar
AU - Malin, Justin
AU - Kumar, Rajesh
AU - Schultz, Christopher W.
AU - Goyal, Shubhank
AU - del Rivero, Jaydira
AU - Krishnamurthy, Manan
AU - Upadhyay, Deep
AU - Schroeder, Brett
AU - Sissung, Tristan
AU - Tyagi, Manoj
AU - Kim, Jung
AU - Pommier, Yves
AU - Aladjem, Mirit
AU - Raffeld, Mark
AU - Douglas, William
AU - Trepel, Jane
AU - Xi, Liqiang
AU - Desai, Parth
AU - Thomas, Anish
N1 - ©2023 American Association for Cancer Research.
PY - 2023/9/15
Y1 - 2023/9/15
N2 - PURPOSE: 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.PATIENTS AND METHODS: 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.RESULTS: 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.CONCLUSIONS: 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.
AB - PURPOSE: 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.PATIENTS AND METHODS: 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.RESULTS: 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.CONCLUSIONS: 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.
KW - Camptothecin/adverse effects
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Humans
KW - Immunoconjugates/adverse effects
KW - Lung Neoplasms/drug therapy
KW - Male
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:001076401300001&DestLinkType=FullRecord&DestApp=WOS_CPL
UR - https://www.scopus.com/pages/publications/85171393721
U2 - 10.1158/1078-0432.CCR-23-0536
DO - 10.1158/1078-0432.CCR-23-0536
M3 - Article
C2 - 37227187
SN - 1078-0432
VL - 29
SP - 3603
EP - 3611
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -